Chelerythrine ameliorates renal injury in diabetic nephropathy rats by enhancing autophagy and modulating AMPK/mTOR signaling with concurrent anti-inflammatory and anti-fibrotic actions.

Diabetic nephropathy (DN) causes end-stage renal disease. Chelerythrine is renoprotective, but the pathway linking AMPK/mTOR, autophagy, inflammation, and fibrosis remains undefined. To define the molecular pathway through which chelerythrine protects diabetic rat kidneys. Male rats received streptozotocin (55 mg/kg) and were assigned to normal control, diabetic control, chelerythrine 10 mg/kg, 20 mg/kg, or metformin 500 mg/kg for 42 days. Metabolic parameters, renal function, and histology were recorded. Molecular endpoints were quantified by qPCR and immunohistochemistry. Chelerythrine lowered fasting glucose, serum creatinine, blood urea nitrogen, urinary protein, and NGAL relative to diabetic controls. At the signalling level, chelerythrine activated AMPK, demonstrated by increased p-ACC (Ser79), and concomitantly suppressed mTORC1, indicated by decreased p-p70S6K (Thr389). Autophagic flux was restored, evidenced by higher LC3-II, Beclin-1, and ATG5 mRNA together with lower p62 protein. Inflammatory activity fell, with reduced TNF-α, IL-6, IL-1β, diminished p-NF-κB p65 (Ser536), and decreased Nlrp3 mRNA. Fibrotic signalling was attenuated, shown by lower TGF-β, α-SMA, collagen IV, reduced p-Smad2/3, and decreased Col1a1 mRNA. Chelerythrine confers multitarget renoprotection in DN. It activates the AMPK-p-ACC pathway, inhibits mTORC1 via reduced p-p70S6K, restores autophagy (LC3-II, Beclin-1, ATG5, p62), and subsequently limits inflammation through p-NF-κB/Nlrp3 and fibrosis through p-Smad2/3/Col1a1 suppression. These data support chelerythrine as potential adjunct or alternative to current DN therapies.