Advances in α-Lipoic Acid for Disease Prevention: Mechanisms and Therapeutic Insights.

1. Introduction

α-Lipoic acid (ALA), also known as lipoic acid (LA), is a naturally occurring bioactive compound with multifunctional therapeutic properties, first isolated from the liver tissue in 1951 by Reed et al. [ 1 ]. The single chiral center at the C6 position of ALA results in two enantiomeric forms: (S)-ALA and (R)-ALA. The R-ALA is a naturally occurring form and predominates in mediating the biological activity of ALA [ 2 ]. ALA and its reduced form, dihydrolipoic acid (DHLA), form a stable redox pair, which is interconverted in vivo through enzymatic pathways, including disulfide dehydrogenase, thioredoxin reductase, and glutathione reductase [ 3 ]. ALA is found in various food sources, including red meat and plants [ 4 ]. Due to its hydrophilic and hydrophobic properties, ALA can function effectively in cell membranes and the cytoplasm [ 5 ]. Although dietary sources of ALA are limited, exogenous intake can enhance its systemic levels, thereby supporting its therapeutic applications [ 6 ] ( Figure 1 ).

This review presents a comprehensive analysis of the diverse therapeutic potential of ALA by integrating the recent advancements. It provides an updated perspective on ALA-related therapies, with a particular emphasis on its applications in the treatment of neurodegenerative disorders, pulmonary diseases, cardiovascular conditions, and diabetes. In addition, the review highlights the development of novel therapeutic strategies, including ALA derivatives and advanced drug delivery systems, underscoring their promise in clinical applications. Furthermore, it emphasizes the necessity of the further optimization of delivery systems and translational applications. By bridging mechanistic insights with therapeutic innovation, this review aims to offer new directions for ALA-based interventions and support advances in effective clinical treatment strategies.

2. Biological Functions of ALA

ALA is the only known antioxidant with both water and lipid solubility, known as the “universal antioxidant”. This unique property enables ALA to enhance the body’s antioxidant capacity through various mechanisms, including the direct scavenging of free radicals, regeneration of endogenous antioxidants, chelation of metal ions, and modulation of inflammatory responses ( Figure 2 ).

2.1. Scavenging Free Radicals

Previous studies discovered that reactive oxygen species (ROS), reactive nitrogen species (RNS), and highly reactive free radicals (•OH, •O 2 − , •NO) produced during aerobic metabolism or stress responses can be effectively neutralized by ALA through direct hydrogen donation or redox cycling mechanisms [ 7 ]. It has been reported that the addition of ALA in sperm washing media maintained sperm viability and motility by reducing ROS generation and preserving sperm DNA integrity [ 8 ]. Furthermore, supplementation with two antioxidants, ALA and N-acetyl-l-cysteine, has been shown to reduce retinal ROS levels and repair damaged mitochondria, thereby improving retinal functions. These findings support the potential of antioxidant supplementation as an effective intervention strategy for individuals experiencing sleep deprivation [ 9 ]. In an Alzheimer’s disease model, ALA has been demonstrated to inhibit the formation of •OH and reduce the expression of inducible nitric oxide synthase (iNOS) and nitric oxide (NO), thereby indirectly mitigating disease progression [ 10 ]. Additionally, DHLA effectively scavenges superoxide anions and peroxyl free radicals, preventing free radical-mediated protein oxidation [ 11 ]. Therefore, ALA is considered to exert cytoprotective effects against oxidative stress by scavenging these reactive species.

2.2. Regeneration of Other Antioxidants

Antioxidants are oxidized during the process of neutralizing free radicals, temporarily losing their scavenging ability until they are subsequently reduced. DHLA, as the reduced form of ALA, mitigates oxidative damage by regenerating endogenous antioxidants, including vitamin E, vitamin C, and glutathione (GSH) [ 12 ]. Moreover, the DHLA-mediated reduction of the oxidized form of coenzyme Q10 contributes to the reduction of α-tocopherol free radical generation [ 13 ]. Therefore, ALA provides valuable therapeutic approaches for diseases related to free radicals by increasing cellular glutathione levels and participating in the redox of antioxidants (vitamins E and C) [ 5 ].

2.3. Metal Chelator

The ability of ALA to form complexes with redox-active metal ions has been well established. Previous studies have demonstrated that ALA effectively chelates divalent metal ions, including Cu 2+ , Fe 2+ , Zn 2+ , Mn 2+ , Cd 2+ , and Pb 2+ , which in turn contributes to the prevention and treatment of cellular toxicity caused by metal ion deposition [ 14 ]. ALA treatment has been shown to reverse iron deposition, oxidative stress, and the increase in autophagy induced by ferrous ammonium citrate [ 15 ]. In the context of copper-induced neurotoxicity, the co-administration of monoisopropyl-DMSA (MiADMSA) and ALA provides a more effective treatment strategy than either MiADMSA or ALA alone [ 16 ]. In summary, ALA offers therapeutic benefits by reducing metal-induced oxidative damage and enhancing antioxidant activity through metal chelation.

2.4. Anti-Inflammatory

Inflammation is a consequence of an innate biological response triggered by an organism’s exposure to harmful stimuli. It is a protective mechanism to eliminate injurious factors and preserve tissue integrity. However, when inflammation becomes chronic, it contributes to the development and progression of various diseases [ 17 ]. ALA has been demonstrated to exert anti-inflammatory effects by directly modulating specific signaling pathways. It is reported that ALA protects against hepatic inflammation, as evidenced by reduced hepatic levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which are associated with the upregulation of nuclear factor erythroid 2-related factor 2 (NRF2) and inhibition of nuclear factor-κB (NF-κB) signaling [ 18 , 19 ]. In addition, treatment with dihydrolipoic acid-coated gold nanoclusters (DHLA-Au NCs) inhibits the activation of JNK and its downstream target c-Jun, subsequently suppressing AP-1-mediated TNF-α expression, thereby contributing to the attenuation of cellular inflammation and senescence [ 20 ]. Costa et al. [ 21 ] found that ALA alleviates irinotecan-induced inflammation in the duodenum, characterized by elevated levels of IL-6 and IL-1β.

3. Pharmacological Application of ALA

The antioxidant, anti-inflammatory, and metal-chelating properties of ALA have positioned it as a key candidate for the therapy of various diseases, including neurodegenerative disorders, pulmonary fibrosis, lung cancer, and cardiovascular diseases, providing a theoretical basis for clinical applications. Although clinical studies remain limited, existing data and experimental findings have demonstrated its potential therapeutic benefits. Additionally, ALA has been shown to effectively improve diabetic symptoms, alleviate diabetic neuropathy, and prevent the development of diabetic cataracts.

3.1. Neurodegeneration

Neurodegenerative diseases (NDs) are a group of neurological disorders characterized by the loss of neuronal function in the central or peripheral nervous system, leading to functional impairment [ 22 ]. Due to the heterogeneity of clinical manifestations and the diversity of potential pathogenic mechanisms, there is an urgent need for effective interventions to overcome the challenges in developing therapeutic strategies for NDs [ 23 ]. Recent studies have reported promising findings about the potential therapeutic effects of ALA in NDs, which are summarized in Table 1 .

3.1.1. Alzheimer’s Disease

Relatively rare but noteworthy reports have found that daily administration of ALA (600 mg) to 43 patients with Alzheimer’s disease (AD) significantly slowed disease progression in those with mild dementia over a 48-month observation period [ 36 ]. Furthermore, another clinical study reported that treatment with 600 mg/day ALA combined with omega-3 fatty acids significantly attenuated cognitive and functional decline in 39 AD patients over 12 months [ 37 ]. In recent years, evidence suggested that ALA improves mitochondrial dysfunction in AD cells by increasing the activity of diversified complexes in the respiratory chain, thereby enhancing mitochondrial membrane potential (MMP) and increasing ATP levels [ 24 ]. Metsla et al. [ 25 ] reported that ALA supplementation facilitates the transport of copper from extracellular to intracellular, alleviating the intracellular copper deficiency of AD neurons. Moreover, ALA has been shown to protect against the development of AD by improving the motor activity of fruit flies with human Aβ overexpression. Another study demonstrated that ALA administration significantly ameliorates scopolamine-induced memory impairment and exploratory behavior by reducing acetylcholinesterase activity and correcting the abnormal levels of amines in the hippocampus and prefrontal cortex [ 26 ]. Additionally, ALA exhibited neuroprotective effects by effectively inhibiting apoptosis, morphological changes, and inflammatory responses in BV2 ( Figure 3 A,B) [ 27 ], as well as regulating the Wnt/β-catenin pathway in PC12 cells activated by Aβ 25–35 [ 28 ]. Mechanistically, ALA improved the cognitive deficits of APP23/PS45 transgenic mice by promoting the maturation of ADAM10 and α-cleavage of APP via BNIP3L-mediated autophagy ( Figure 3 C) [ 29 ]. Therefore, targeting anti-inflammation and mitochondrial functions may represent a promising strategy for the treatment of AD.

3.1.2. Parkinson’s Disease

Previous studies have shown that ALA alleviates the motor deficits in Parkinson’s disease (PD) models by regulating iron metabolism, including the upregulation of ferritin heavy chain (FTH1) and ferroportin (FPN), as well as the downregulation of divalent metal transporter 1 (DMT1). Additionally, ALA mitigates ferroptosis through the SIRT1/NRF2 signaling pathway ( Figure 3 D,E) [ 30 ]. Notably, ALA has been shown to promote the survival of dopaminergic neurons and mitigate motor deficits by decreasing the intracellular ROS and iron levels, as well as inhibiting the decline in superoxide dismutase (SOD) activity and tyrosine hydroxylase (TH) expression [ 31 ]. Exposure to ALA, an activator of PGC1α, enhanced the cognitive function in PD rats by increasing mitochondrial biogenesis and modulating neuroinflammatory pathways, accompanied by reduced oxidative stress and inflammatory levels [ 32 ]. Moreover, ALA prevented 6-tetrahydropyridine-induced neurotoxicity in vitro and in vivo by upregulating the expression of SIRT1 and PGC1α [ 33 ]. Additionally, MPTP-induced motor dysfunction in mice was significantly alleviated by ALA through a reduction in NF-κB, TNF-α, and iNOS in the substantia nigra and spinal cord [ 34 ]. In PC12 cells, ALA alleviated the decrease in cell viability and ferroptosis induced by MPP+ through stimulation of the PI3K/AKT/NRF2 pathway ( Figure 3 F,G) [ 35 ].

This evidence strongly supports the therapeutic potential of ALA in NDs, highlighting its ability to enhance mitochondrial function, regulate iron metabolism, modulate inflammation, and prevent apoptosis. These properties, coupled with its capacity to interact with critical signaling pathways, position ALA as an innovative therapeutic strategy for complex NDs. Future clinical trials are essential to determine how these preclinical benefits translate into the treatment of human diseases, as well as exploring the potential of combination therapies for optimizing therapeutic efficacy.

3.2. Pulmonary Diseases

Lung cancer is the leading cause of cancer-related death, with its incidence and mortality rates rising annually, posing a substantial threat to human life [ 38 ]. Pulmonary fibrosis (PF) is a chronic, interstitial lung disease characterized by fibroblast proliferation and excessive extracellular matrix (ECM) deposition, leading to a gradual decline in lung function and respiratory distress. Notably, the relative incidence of lung cancer is appreciably higher in patients with PF compared to those without PF, with reported rates ranging from 4.4% to 13% and as high as 48% in autopsy samples [ 39 ]. Therefore, early intervention and integrated management strategies that address PF and lung cancer could improve patient survival and quality of life. In recent years, accumulating preclinical studies have investigated the role of ALA in both pulmonary fibrosis and lung cancer ( Table 2 ).

3.2.1. Pulmonary Fibrosis

Exogenous ALA was found to alleviate silica-induced pulmonary fibrosis through activation of the AMPK/PGC1α pathway, which enhanced mitochondrial function and reduced the production of ROS in mice ( Figure 4 A) [ 40 ]. Yan et al. [ 41 ] reported that the low expression of lipoic acid synthase (LIAS) aggravated pulmonary fibrosis caused by SiO 2 , while ALA supplementation promoted an immune balance between Th17 and Treg responses, reducing the accumulation of ECM and inflammatory cells in lung tissues, alleviating silicosis fibrosis. Furthermore, treatment with ALA and the endogenous overexpression of LIAS mitigated chronic inflammatory responses and enhanced antioxidant defenses, protecting against amiodarone- ( Figure 4 B) [ 42 ] or silica-induced pulmonary fibrosis [ 43 ]. Elhadidy et al. [ 44 ] discovered that ALA alleviated the pulmonary cytotoxicity of busulfan through the upregulation of cyclooxygenase-2 (COX-2) and downregulation of NADPH oxidase-4 (NOX-4) expression. The lung injury following radiation was mitigated by ALA, as indicated by the reduced infiltration of most inflammatory cells, edema, alveolar damage, and fibrosis [ 45 ]. This highlights the potential of ALA as a versatile player by simultaneously addressing the inflammation and fibrotic components in pulmonary fibrosis.

3.2.2. Lung Cancer

As an antioxidant, ALA has attracted considerable attention in cancer research. It has been shown that ALA inhibits the progression of lung cancer by suppressing autophagy in A549 cells, a process mediated by activation of the mTOR/p70S6K pathway ( Figure 4 C–E) [ 46 ]. Moreover, ALA depletes Oct-4 and β-catenin by reducing the levels of p-AKT, thereby inhibiting epithelial–mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC) cells [ 47 ]. Yang et al. [ 48 ] demonstrated that ALA inhibits tumorigenesis by reducing GRB2-mediated EGFR and ERK1/2 phosphorylation in NSCLC. Additionally, ALA sensitized NSCLC cells to apoptosis by downregulating the expression of PDK1, leading to a reduction in NRF2 levels and an enrichment of mitochondrial ROS [ 49 ]. In combination with cisplatin, etoposide, and paclitaxel, ALA increased the sensitivity of lung cancer cells to apoptosis by downregulating integrin β1 and β3, which are related to invasive behavior and metastasis [ 50 ].

Taken together, the present findings emphasize the versatility of ALA in the therapy of pulmonary fibrosis and lung cancer. Its dual ability to modulate the redox balance and immune responses highlights the therapeutic promise of ALA in addressing these complex diseases. However, these studies assume a linear pathway of action, but the complexity of ROS-mediated pathways and the potential for off-target effects in humans remains to be fully elucidated.

3.3. Cardiovascular Diseases

Cardiovascular diseases represent a serious threat to global health, characterized by high incidence, substantial disability, and elevated mortality, making it the leading cause of death worldwide [ 51 ]. Recent studies have highlighted the potential of ALA as a cardioprotective agent, as summarized in Table 3 .

3.3.1. Myocardial Infarction

The daily oral administration of ALA has been shown to significantly reduce oxidative stress and improve the left ventricular ejection fraction (LVEF) and left ventricular end-systolic volume (LVESV) in mice with acute myocardial infarction (AMI). Moreover, the survival rate of mice with AMI treated with ALA was increased by 63% [ 52 ]. Furthermore, ALA attenuated MI by inducing M2b macrophage polarization through HMGB1/NF-κB-pathway-mediated inflammation, oxidative stress, autophagy, and apoptosis, providing a hopeful strategy for the treatment of MI ( Figure 5 A,B) [ 53 ]. Nemati et al. [ 54 ] proposed that the combined intervention of Mito Q and ALA synergistically improves cardiac function in aged MI rats by suppressing inflammation and apoptosis ( Figure 5 C). Additionally, supplementation with ALA was found to improve isoproterenol-induced MI injury, reducing mortality and the incidence of ventricular arrhythmias in experimental MI [ 55 ].

3.3.2. Myocardial Ischemia–Reperfusion

A recent study has highlighted the significant therapeutic potential of combining MitoQ and ALA in protecting aged rats from ischemia/reperfusion (IR) injury by enhancing oxidative stress resistance and improving mitochondrial functions in aged rats [ 56 ]. In diabetic hearts, ALA pretreatment significantly restored postconditioning-induced cardiac protection by modulating oxidative stress, autophagy, and the recovery of mitochondrial function [ 57 , 58 ]. In addition, the simultaneous use of ALA and postconditioning promoted the recovery of diabetic hearts after I/R by inhibiting apoptosis, as evidenced by increased protein expression of cleaved Caspase-3 and BAX, alongside reduced expression of BCL-2 [ 59 ]. Moreover, Qi et al. [ 60 ] reported that ALA regulated the translocation of HMGB1 through the HMGB1/TLR4/NF-κB pathway, preventing apoptosis and oxidation, thus inhibiting myocardial IR injury ( Figure 5 D). Therefore, the combination of ALA with other interventions may serve as an effective strategy to attenuate cardiac I/R damage.

3.3.3. Heart Failure

Cardiac remodeling, driven by various cardiovascular diseases, can progress to heart failure in advanced stages. Although limited, some studies have explored the therapeutic effects of ALA on heart failure. Pop et al. [ 61 ] demonstrated that intermittent ALA treatment alleviates glucose and lipid metabolic disorders in rats, protecting against heart failure through known antioxidant effects and its inherent anti-obesity and anti-inflammatory properties. Furthermore, ALA was shown to mitigate left ventricular hypertrophy and dysfunction induced by transverse aortic constriction (TAC) in mice. This protective effect was attributed to the activation of the NRF1/FUNDC1 pathway, which enhanced the activity and expression of ALDH2 ( Figure 5 E) [ 62 ].

In summary, current findings highlight the multifaceted cardioprotective properties of α-lipoic acid in mitigating myocardial infarction, ischemia-reperfusion injury, and heart failure. ALA’s actions extend beyond mere antioxidant effects, influencing key signaling pathways involved in inflammation, apoptosis, and metabolic regulation. The combination of ALA with other therapeutic agents, such as MitoQ, further enhances its cardioprotective potential. However, further comprehensive and rigorous studies are required to confirm these effects and fully elucidate the underlying mechanisms.

3.4. Diabetes

Metabolic diseases, particularly diabetes and its associated complications, profoundly impair individuals’ quality of life. Among these complications, diabetic polyneuropathy (DPN) and diabetic retinopathy are especially prevalent, leading to the significant deterioration of neurological functions and visual acuity. Accumulating studies have elucidated the underlying mechanisms and clinical applications of ALA in attenuating the progression of diabetes and its complications ( Table 4 ), highlighting its potential as a promising therapeutic agent in the management of diabetes.

DPN is closely associated with elevated cellular ROS production and the extent of endothelial dysfunction in patients with T2DM [ 63 , 64 ]. ALA has been demonstrated to alleviate DPN symptoms by reducing oxidative stress and improving microcirculatory functions. The Neurological Assessment of Thioctic Acid in Diabetic Neuropathy (NATHAN 1) trial showed that the long-term oral administration of ALA over a period of 4 years produced clinically meaningful improvements and modestly delayed the progression of neurological deficits in patients with DPN [ 65 ]. Additionally, a 6-month intervention with oral ALA (600 mg/day) significantly reduced advanced glycation end products (AGEs), increased the current perception threshold and granulocyte protein levels, and decreased asymmetric dimethylarginine (ADMA), thereby improving vascular endothelial function and alleviating the neuropathic symptoms of type 2 diabetes mellitus (T2DM) patients with neuropathy [ 66 ]. In a randomized, single-center, double-blind, placebo-controlled clinical trial, the oral administration of 600 mg/kg ALA twice daily for over 6 months resulted in significant symptomatic improvements in DPN patients. Moreover, mild nausea was reported in six patients. No participants discontinued treatment. This clinical trial further confirmed the efficacy, safety, and tolerability of ALA for the treatment of DPN [ 67 ]. In a study involving 1242 patients, the administration of different doses of ALA (600, 200, and 1800 mg/day) significantly alleviated sensory symptoms and favorably impacted diabetic sensorimotor peripheral neuropathy (DSPN). A dose-dependent improvement was observed in both the total symptom score (TSS) and the global satisfaction score compared with the placebo [ 68 ]. Furthermore, in a study of 54 T2DM patients with DSPN, six months of ALA administration (600 mg/day) resulted in decreased levels of serum kallistatin, TNF-α, and ADMA. A positive correlation was identified between changes in kallistatin and oxidized low-density lipoprotein (oxLDL) levels. These findings suggest that kallistatin may serve as a potential biomarker for evaluating the therapeutic response to ALA in patients with DSPN [ 69 ].

Individuals with diabetes have a 25-fold increased risk of blindness and early cataracts compared to the general population, with approximately 20% of diabetic patients developing cataracts [ 70 ]. Although relatively uncommon, several reports have highlighted the potential of ALA to delay the formation of diabetic cataracts. It is reported that the weekly administration of ALA at a dose of 10 mg/kg in diabetic mice reduced the incidence of grade 2 cataract formation from 100% to 71% [ 71 ]. The primary mechanism underlying cataract development in diabetes involves the generation of sorbitol, a sugar alcohol produced via the action of aldose reductase (AR). The inhibition of AR is therefore considered a promising strategy for preventing diabetic cataracts. ALA, acting as both an antioxidant and an AR inhibitor, has been shown to delay the development and progression of diabetic cataracts by reducing oxidative stress and potentially inhibiting protein glycation [ 72 ]. A prospective, placebo-controlled, double-blind study demonstrated that oral administration of Ocu-GLO Rx™, a commercially available antioxidant formulation containing ALA and other antioxidants, exerted beneficial effects on the reduction in cataract progression in diabetic dogs [ 73 ]. Notably, diabetic dogs supplemented with ALA alone exhibited a decrease in lens opacities and a significant delay in cataract formation, thereby slowing and potentially preventing the onset of cataract [ 74 ]. These findings suggest that by inhibiting AR activity and modulating the polyol pathway, ALA may play an important role in the prevention and treatment of diabetic cataracts.

Overall, the multifaceted pharmacological properties of ALA, including its antioxidant activity, modulation of endothelial function, and inhibition of aldose reductase, highlight its potential as a promising adjunctive therapy in the comprehensive management of diabetes-related complications, such as neuropathy and retinopathy. Nevertheless, the majority of current evidence is derived from short-term clinical trials and animal model studies, with the long-term efficacy and safety of ALA remaining insufficiently established. Future studies should aim to elucidate the optimal dosing strategies, assess long-term safety profiles, and evaluate the clinical utility of molecular biomarkers, such as kallistatin, for personalized treatment monitoring, thereby minimizing adverse effects and enhancing therapeutic outcomes.

4. Novel Therapeutic Strategies of ALA

Despite its potential in treating various diseases, the clinical efficacy of ALA is limited due to challenges of low bioavailability and poor stability. Therefore, chemical modifications and advanced delivery systems have been explored to improve its stability and absorption.

4.1. Derivatives of ALA

Recent advances in pharmacological research have highlighted several ALA derivatives with promising therapeutic potential in various preclinical and clinical models due to their distinctive mechanisms ( Figure 6 ).

4.1.1. N2L

N2L ( Figure 6 A), a specific dimer of ALA formed by the linkage of two ALA molecules via a disulfide bond, was synthesized by Chen et al. [ 75 ] in 2014 with the aim of enhancing the biological activity of ALA and improving its therapeutic properties. N2L has been shown to exert neuroprotective effects against Aβ1–42-induced cytotoxicity by restoring the activities of GPX, SOD, and CAT to suppress oxidative stress, while inhibiting apoptosis by upregulating BCL-2 protein levels and downregulating cleaved Caspase-3 and BAX protein expression [ 76 ]. Additionally, high doses of N2L (>100 mol/L) decrease oxidative damage to hRPE cells exposed to blue light through the upregulation of BCL-2 and downregulation of Caspase-3 and BAX [ 77 ]. As a potent and selective high-affinity agonist of the niacin receptor GPR109A, N2L has demonstrated favorable effects in regulating lipid metabolism and inhibiting atherosclerosis. It also exhibited excellent antioxidant properties, maintaining a favorable safety profile [ 78 ]. Furthermore, N2L protects HT22 cells from RSL3-induced ferroptosis by inhibiting activation of the JNK/ERK signaling pathway, diminishing lipid peroxidation through the restoration of GPX4 expression, and the reduction of ACSL4 and COX-2 protein levels [ 79 ].

4.1.2. L-F001

L-F001 ( Figure 6 B), a multifunctional fasudil-ALA dimer, effectively prevents paraquat-induced apoptosis by modulating GRP78 and CHOP expression, alleviating mitochondrial dysfunction, and reducing endoplasmic stress in PC12 cells [ 80 ]. It also protects against 6-OHDA-induced PC12 cell death and mitigates MPTP-induced dopaminergic neurotoxicity in mice by activating AKT and GSK-3β phosphorylation, as well as inducing the nuclear translocation of NRF2 and expression of HO-1 in a concentration- and time-dependent manner [ 81 ]. Additionally, L-F001 prevents RSL3-induced ferroptosis by inhibiting JNK activation and maintaining iron homeostasis, which reduces intracellular ROS and lipid peroxidation levels [ 82 ]. Furthermore, L-F001 protects against hypoxic–ischemic brain damage by reducing COX-2 and iNOS expression through inactivation of the TLR4 signaling pathway in HD rats [ 83 ].

4.1.3. CPI-613

CPI-613 ( Figure 6 C), a multitargeted metabolic inhibitor derived from endogenous ALA, targets the dysregulated tricarboxylic acid (TCA) cycle in cancer cells by inhibiting both the α-ketoglutarate dehydrogenase (KGDH) and pyruvate dehydrogenase complex (PDC), which is currently undergoing clinical trials in various malignancies [ 84 ]. It has been found that CPI-613 prevents pancreatic cancer progression by stimulating ROS-mediated apoptosis through activation of the AMPK signaling pathway [ 85 ]. Additionally, the combination of CPI-613 with 5-fluorouracil or irinotecan disrupts the MMP and markedly impairs mitochondrial respiration, leading to colorectal cancer cell death in a Bim-dependent manner [ 86 ]. Another study has suggested that CPI-613 enhances the chemotherapy sensitivity of ovarian cancer cells by inducing mitochondrial dysfunction, triggering mitochondria-mediated apoptosis [ 87 ]. Furthermore, CPI-613 suppresses the proliferation of multiple myeloma cells by inducing mitochondrial metabolic dysfunction through the targeting of pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) and oxoglutarate dehydrogenase (OGDH), and it produces significant anti-tumor effects when combined with bortezomib at a lower dose [ 88 ].

4.1.4. Others

Beyond the widely studied derivatives, other ALA derivatives have also been reported for the management of various diseases. CMX-2043 ( Figure 6 D), a novel ALA analog, appears to be a promising candidate for mitigating myocardial IR injury. Treatment with CMX-2043 was found to reduce myocardial IR injury regardless of whether it was administered prior to ischemic injury or during reperfusion. Notably, the most effective administration was observed when CMX-2043 was given 15 min prior to ischemia, indicating a specific therapeutic window where the compound may exert its protective effects most effectively [ 89 ]. Additionally, a phase II clinical trial demonstrated that CMX-2043 significantly reduced myocardial damage during percutaneous coronary intervention procedures in 142 patients who were randomized to receive either a single intravenous dose of CMX-2043 or a placebo 15–60 min before surgery [ 90 ]. Andrographolide-LA-1 ( Figure 6 E), a compound synthesized through the esterification of andrographolide and ALA, was proposed to be a major transcription factor that significantly reduces the inflammatory response in inflammatory bowel disease [ 91 ]. A phase II clinical trial has demonstrated that although the application of 1% DHL-HisZnNa ( Figure 6 F) does not inhibit chemotherapy-induced alopecia (CIA) in breast cancer patients, it promotes the recovery from CIA [ 92 ]. Moreover, DHL-HisZnNa treatment inhibits colorectal cancer cell proliferation through increased p53 phosphorylation and p21 protein levels, as well as decreased levels of phosphorylated retinoblastoma (Rb) [ 93 ]. The continuous subcutaneous administration of DHL-TauZnNa ( Figure 6 G) for 41 days significantly inhibited colon cancer cell proliferation via G2/M cell cycle arrest and the induction of excessive autophagy [ 94 ].

The development of ALA derivatives has expanded the therapeutic potential of ALA beyond its antioxidant properties. These derivatives exhibit a diverse range of mechanisms, including antioxidant activity, ferroptosis inhibition, mitochondrial dysfunction, and the modulation of key signaling pathways, such as AKT, GSK-3β, NRF2, and TLR4. These data suggest that ALA derivatives hold promise for treating a variety of diseases, from neurodegenerative disorders to cardiovascular diseases and cancers. Further clinical trials and mechanistic studies are needed to fully elucidate the therapeutic efficacy and safety profiles of these novel compounds.

4.2. Delivery Systems of ALA

The amphiphilicity of ALA facilitates efficient cellular uptake and membrane penetration, enhancing its effectiveness as both an antioxidant and a component in drug formulations. Furthermore, ALA’s ability to form disulfide-linked dimers plays a crucial role in stabilizing drug delivery systems. These unique properties position ALA as a promising candidate for optimizing drug delivery systems.

4.2.1. Nanoparticles

Nanoparticle (NP)-based systems have been shown to enhance the stability and bioavailability of ALA [ 95 ]. Liposomes encapsulating R-ALA (LIP/RLA) have demonstrated enhanced oral absorption and bioavailability, improving hepatoprotective effects in rats with liver injury [ 96 ]. The administration of AlCl3 significantly elevates neuroinflammation, oxidative stress, and apoptosis, while reducing brain fatty acid content. These adverse effects were effectively ameliorated by ALA, ALA-loaded chitosan nanoparticles (ALA-CsNPs), and ALA-loaded solid lipid nanoparticles (ALA-SLNPs). Notably, the ALA nanoparticles exhibit more pronounced therapeutic effects compared to free ALA [ 97 ]. Additionally, the systemic administration of MC-PαLA-MP NPs for 8 weeks provides effective neuroprotection and preserves motor function by alleviating inflammation after experimental traumatic spinal cord injury in rats ( Figure 7 A) [ 98 ]. PEGylated hollow gold nanoparticles loaded with ALA (mPEG@HGNPs-ALA) effectively scavenge ROS induced by H 2 O 2 injury and enhance cell viability, thereby facilitating the treatment of osteoporosis ( Figure 7 B) [ 99 ].

4.2.2. Hydrogels

Hydrogel systems that encapsulate ALA or its derivatives enable controlled release and offer enhanced therapeutic benefits in various diseases, owing to their potent biological activity. A self-stabilized deep eutectic supramolecular polymer (LA-DESP) prepared in one step by heating a mixture of AL and ALA-Na demonstrated rapid and strong adhesion to various substrates. It functions as a tissue adhesive, replacing surgical sutures and promoting wound healing ( Figure 8 A) [ 100 ]. Furthermore, an injectable hydrogel based on hyaluronic acid, chitosan, and potassium-γ-cyclodextrin metal-organic frameworks (K-γ-CD-MOFs) loaded with ALA demonstrated both antioxidant and antibacterial properties. By promoting cell migration and proliferation, it effectively mitigated oxidative stress-induced cellular damage, facilitating the healing of chronic full-thickness skin wounds [ 101 ]. ALA-modified chitosan (LAMC) and melanin nanoparticle (MNP) (LAMC@MNPs) hydrogels not only exhibit excellent skin adhesion but also effectually attenuate oxidative stress by scavenging radicals, which accelerates wound healing ( Figure 8 B) [ 102 ]. Additionally, ALA and trimethylglycine expeditiously form supramolecular hydrogels at room temperature, exhibiting injectability and the potential for 3D printing. A hydrogel bandage derived from this system significantly enhanced wound healing by facilitating wound closure, creating a protective physical barrier and providing anti-inflammatory effects [ 103 ]. Furthermore, poly (lipoic acid-co-sodium lipoic acid) (PLAS) was directly obtained in aqueous solution via ring-opening polymerization triggered by heat and concentration, benefiting from the dynamic disulfide bonds in ALA. PLAS hydrogels exhibited promising antioxidant efficiency, efficiently scavenging intracellular ROS and protecting against spinal cord injury [ 104 ]. A multifunctional poly (lactic acid)-based hydrogel was constructed through the one-step heating of an ALA/arginine/silk fibroin mixture. This hydrogel, when implanted into the body or applied to the skin of mice, effectively prevented postoperative tumor recurrence and facilitated the treatment of radiation-induced skin injuries after radiotherapy in breast cancer ( Figure 8 C) [ 105 ]. When incorporating COS into an ALA hydrogel (COS@LA-hydrogel), as depicted, this hydrogel was gradually degraded in the reducing environment at the implantation site, releasing both LA and COS. The combined action of LA and COS on tumor cells inhibits the phosphorylation of AKT within the PI3K–AKT pathway, thereby preventing the progression of residual tumor cells and resulting in a pronounced antitumor effect [ 106 ].

4.2.3. Electrospinning

Electrospinning is a widely recognized technique for fabricating micrometer-thick films consisting of submicron nanofibers and polymers, which allows for precise manipulation of the fiber diameter and distribution, making it highly suitable for biomedical applications [ 107 ]. Recently, an electrospinning technique has been employed to prepare nanofiber-based delivery systems, further enhancing the efficacy of ALA in treating oxidative stress and inflammatory conditions [ 108 ]. A nano-flower-like MoS2, synthesized via electrochemical methods, was functionalized with ALA and chitosan oligosaccharide to create a composite material (MoS2-LA-COS) with high biocompatibility, good dispersion, and near-infrared (NIR) light responsivity. This material was effectually attached to an electrospun nanofiber membrane, endowing the fiber scaffold with excellent photothermal performance and exhibiting significant antibacterial effects under NIR light irradiation ( Figure 9 A) [ 109 ]. The electrospun nanofibers (PUL/LA/M-β-CD NF), prepared by combining pullulan (PUL) with LA-M-β-CD, effectively reduced the production of ROS by downregulating COX-2 and iNOS in LPS-treated RAW 264.7 cells. Additionally, these nanofibers inhibited pro-inflammatory cytokine expression (IL-1β, TNF-α, and IL-6) and NF-κB nuclear translocation, highlighting the significant potential for oral anti-inflammatory treatment ( Figure 9 B) [ 110 ]. Poly (lactic acid-co-glycolic acid) (PLGA) copolymers were utilized as carriers to form films (LA@PLGA) via electrospinning, enabling the controlled release of ALA and effectively blocking the production of ROS in damaged hearts. Thus, LA@PLGA significantly improved cardiac function in mice with acute myocardial infarction through its strong anti-apoptotic and antioxidant activity ( Figure 9 C) [ 111 ].

The integration of ALA into various advanced drug delivery systems, such as nanoparticles, hydrogels, and electrospun nanofibers, has enhanced its therapeutic efficacy in treating a wide range of diseases, including neurodegenerative disorders, cancer, cardiovascular diseases, and chronic wounds. These delivery systems leverage ALA’s unique properties, such as its amphiphilicity, antioxidant capacity, and ability to form disulfide-linked dimers, to optimize drug stability, bioavailability, and controlled release. Future research should focus on optimizing the design and fabrication of these systems to improve their therapeutic outcomes, explore their potential in clinical settings, and further investigate their safety profiles.

5. Conclusions

The unique ability of ALA to function as both a hydrophilic and hydrophobic compound enhances its versatility as a therapeutic agent. This dual characteristic enables ALA to target a wide range of cellular and molecular processes, positioning it as an available therapeutic option for treating complex diseases with multifactorial pathologies. However, the relatively low bioavailability remains a challenge for the therapeutic application of ALA. The development of novel ALA derivatives and the incorporation of ALA into biomaterials provide novel and promising strategies to improve the efficacy and therapeutic potential of ALA-based therapies. Breakthroughs in these technologies not only overcome the inherent limitations of ALA but also expand its potential applications in modern medicine.

Despite the considerable therapeutic potential of ALA in diverse diseases, further investigation is required to address the challenges and opportunities it presents. First, the clinical efficacy can be improved by optimizing the bioavailability and pharmacokinetics of ALA through innovative therapies, such as advanced ALA derivatives or delivery systems. Second, additional mechanistic studies are necessary to elucidate the precise molecular pathways by which ALA and its derivatives, particularly in multifactorial diseases like cardiovascular diseases and cancer. Additionally, large-scale, well-designed clinical trials are essential to validate the preclinical findings and establish standardized dosing regimens. Exploring synergistic combinations of ALA with existing therapeutic agents may also offer new treatment strategies. Finally, a comprehensive evaluation of the long-term safety and potential adverse effects of ALA-based interventions are critical for their successful translation into clinical practice. Addressing these gaps will not only advance our understanding of ALA but also broaden its potential applications in precision medicine.

Acknowledgments

We would like to extend our gratitude to BioRender ( https://www.biorender.com/learn , accessed on 22 February 2025) for providing the materials used in the preparation of the figures.

Abbreviations

The following abbreviations are used in this manuscript:

Author Contributions

All authors contributed to the study’s conception and design. Figures and table preparation was performed by Y.H. The first draft of the manuscript was written by Y.W. and S.J. The finalized manuscript was revised by P.P. and H.S. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

Funding Statement

This work was supported by the National Natural Science Foundation of China (82170299).

Footnotes

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Associated Data

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.