Oxidative stress and inflammation in renal fibrosis: Novel molecular mechanisms and therapeutic targets.

Renal fibrosis, a hallmark of acute kidney injury (AKI), chronic kidney disease (CKD) and AKI-to-CKD transition, is characterized by the excessive accumulation and deposition of extracellular matrix components, tubular atrophy, tubulointerstitial fibrosis and glomerulosclerosis, that ultimately lead to renal failure. Oxidative stress and inflammation play pivotal roles in renal pathogenesis that form a vicious cycle of cellular injury and fibrotic progression. Accumulating evidence has revealed key molecular mechanisms involved in the fibrotic processes, such as inhibitor of kappa B/nuclear factor kappa B (NF-κB) and Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2), nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), transforming growth factor-β (TGF-β)/Suppressor of Mothers against Decapentaplegic (Smad) and aryl hydrocarbon receptor (AHR) pathways. Novel therapeutic strategies targeting IκB/NF-κB, Keap1/Nrf2, NOX4, TGF-β/Smad and AHR pathways, such as small-molecule inhibitors, antioxidant agents, and antiinflammatory cytokines, show promise in mitigating renal fibrosis. Emerging approaches by targeting epigenetic regulation, non-coding RNAs, gut microbiota and metabolic disorders by chemical drugs (dapagliflozin) and natural compounds (polydatin, dihydromyricetin, baicalin, diosmin, gentiopicroside, hyocholic acid and natural polysaccharides) further expand therapeutic landscape. This review synthesizes recent advances in understanding molecular mechanisms of renal fibrosis and highlights potential therapeutic targets, offering insights into innovative strategies for managing CKD and improving patient outcomes.