Dimethyl fumarate ameliorates high-fat/high-cholesterol diet-induced renal lipotoxicity in association with increased TFEB nuclear translocation, improved lysosomal acidification, and enhanced autophagy-lysosome function

Obesity is a major risk factor for chronic kidney disease, and the autophagy-lysosome pathway has emerged as a tractable therapeutic target in obesity-associated renal dysfunction. We previously showed that dimethyl fumarate (DMF) alleviates renal lipotoxic stress by limiting oxidative damage; however, whether DMF improves autophagy-lysosome competence under lipotoxic stress remained unclear. Here, using a high-fat/high-cholesterol (HFHC) diet mouse model and palmitic acid (PA)-challenged HK-2 proximal tubular cells, we found that DMF treatment was associated with increased TFEB nuclear translocation, enhanced lysosomal biogenesis, and improved lysosomal acidification. Under lipotoxic stress, DMF also increased lysosomal degradative capacity, coinciding with changes consistent with improved autophagic flux and more efficient processing of lipotoxic cargo. Consistent with these effects, DMF reduced lipid droplet accumulation, attenuated mitochondrial stress, and preserved mitochondrial homeostasis, accompanied by improved lipid utilization programs. Importantly, BafA1 treatment, which broadly disrupts lysosomal/Autophagy function, blunted multiple DMF-associated improvements in autophagy-related readouts, lipid handling, oxidative stress, mitochondrial perturbation, and Apoptosis. These findings support the involvement of lysosomal acidification and related lysosomal/Autophagy function in the DMF response under lipotoxic stress. Collectively, our data suggest that DMF is associated with attenuation of obesity-related renal lipotoxicity, together with increased TFEB nuclear translocation, improved lysosomal acidification, and enhanced autophagy-lysosome function, thereby supporting further evaluation of DMF as a potential therapeutic candidate for obesity-associated kidney injury.