Diabetic nephropathy (DN) is a leading cause of end-stage kidney disease, but current therapies do not halt its progression. Mitochondrial-derived peptides have garnered attention for their roles in metabolic regulation, yet whether Mitochondrial Open Reading Frame of the 12S rRNA-c (MOTS-c) participates in DN pathogenesis has not been fully elucidated. In this study, MOTS-c treatment led to dose-dependent preservation of urinary albumin-to-creatinine ratio (UACR), accompanied by attenuated tubular injury, diminished lipid deposition, and reduced macrophage accumulation. Transcriptomic analyses revealed significant enrichment of pathways related to senescence and lipid metabolism. Moreover, MOTS-c suppressed p16INK4A, γH2AX, and SA-β-gal activity, while restoring lipid homeostasis through regulation of CPT1A and ADRP. Mechanistically, MOTS-c downregulated LARS1, an established negative modulator of lipophagy, thereby facilitating LC3-mediated clearance of lipid droplets (LDs). LARS1 overexpression in HK-2 cells effectively abrogated these protective phenotypes. Furthermore, co-administration of the autophagy inhibitor 3-MA in db/db mice largely reversed the renoprotective effects of MOTS-c, supporting the functional relevance of lipophagy in this process. Our findings indicate that MOTS-c protects against diabetic kidney injury by downregulating LARS1, thereby promoting lipophagy, reducing lipid deposition, and suppressing tubular senescence. Targeting the LARS1-lipophagy-senescence axis may offer a new strategy for DN treatment.
