Renal lipotoxicity in diabetic and obesity‐associated kidney diseases: Molecular mechanisms and therapeutic targeting

Metabolic disorders, including diabetes mellitus and obesity, have become major global health burdens that significantly increase the risk of kidney disease. A central pathological feature linking these conditions is lipotoxicity-the deleterious effects of lipid overload on cellular and organ function. In the kidney, lipotoxicity contributes to disease pathogenesis through a complex interplay of molecular mechanisms-such as mitochondrial dysfunction, impaired autophagy, oxidative stress, endoplasmic reticulum stress, and sustained inflammatory responses-which are detailed with a focus on their cell-specific effects in podocytes and proximal tubular cells. These pathological processes collectively disrupt renal cellular homeostasis, promote cell death, and drive progressive fibrosis, ultimately leading to functional decline. Despite significant advances in our understanding of metabolic kidney diseases, effective pharmacological interventions specifically addressing renal lipotoxicity remain strikingly limited. Current therapeutic strategies should extend beyond mere lipid reduction to comprehensively address the underlying metabolic dysregulation and its downstream cellular consequences. This review aims to analyse the pathogenic molecular mechanisms and potential therapeutic agents for renal lipotoxicity in diabetic and obesity-associated kidney diseases. It systematically examines the cell-type-specific injury mechanisms, lipotoxicity-induced renal injury, and the available evidence from both preclinical studies and clinical trials of metabolically active agents with renoprotective effects, with a view to offering novel insights and informing future therapeutic strategies for metabolic kidney diseases.