Alpha‑lipoic acid-loaded chitosan nanoparticles ameliorate streptozotocin‑induced diabetic liver injury via Nrf2/HO‑1 activation and TLR4/NF‑κB and JAK2/STAT1 inhibition.

Diabetes mellitus is a chronic metabolic disorder in which persistent hyperglycemia promotes oxidative stress, inflammatory activation, and progressive liver injury. Alpha‑lipoic acid (ALA) is an endogenous and diet‑derived antioxidant with glucose‑lowering and insulin‑sensitizing actions. Still, its therapeutic efficacy is constrained by low oral bioavailability and rapid metabolism. In this context, the present study compared the hepatic pharmacodynamic effects of free ALA and ALA‑loaded chitosan nanoparticles (ALA‑CNPs) in streptozotocin (STZ)‑induced diabetic rats. Here, pharmacodynamic effects refer to the biochemical and molecular actions on hepatic tissue, including modulation of oxidative stress markers, activation of cytoprotective signaling pathways such as Nrf2/HO‑1, and inhibition of pro‑inflammatory cascades (e.g., TLR4/NF‑κB and JAK2/STAT1), which collectively contribute to hepatoprotection. Diabetes was induced by a single intraperitoneal injection of STZ (60 mg/kg). Rats with fasting blood glucose ≥ 250 mg/dL were randomized into six groups (n = 15/group): non‑diabetic control, non‑diabetic + ALA, non‑diabetic + ALA‑CNPs, untreated diabetic, diabetic + ALA, and diabetic + ALA‑CNPs. Treatments were administered once daily for 4 weeks. STZ‑induced diabetes caused marked hyperglycemia, reduced serum insulin, dyslipidemia, increased serum alanine and aspartate aminotransferase activities, enhanced hepatic malondialdehyde, depletion of superoxide dismutase, catalase, glutathione peroxidase, and reduced glutathione, and downregulation of the Nrf2/HO‑1 pathway. These changes were accompanied by elevated hepatic tumor necrosis factor‑α, interleukin‑6, and interleukin‑1β; activation of Toll‑like receptor‑4/nuclear factor‑κB and Janus kinase‑2/signal transducer and activator of transcription‑1 signaling, and hepatocellular necrosis; vacuolation; mitochondrial swelling; and endoplasmic reticulum disorganization. Both ALA and ALA‑CNPs attenuated these metabolic, biochemical, and structural disturbances, but ALA‑CNPs produced more pronounced reductions in fasting blood glucose and improvements in lipid profile, antioxidant status, and liver histology. ALA‑CNPs also more effectively upregulated Nrf2/HO‑1 and suppressed Toll‑like receptor‑4/nuclear factor‑κB and Janus kinase‑2/signal transducer and activator of transcription‑1 activation and pro‑inflammatory cytokines. These findings indicate that nano‑encapsulation of ALA enhances its hepatoprotective pharmacological profile in diabetes‑associated liver injury by concomitantly targeting oxidative stress and inflammatory signaling cascades.