Abnormal lipid metabolism in senescent renal tubular cells in diabetic nephropathy.

Diabetic nephropathy (DN) is a common and severe microvascular complication of diabetes. The stress-induced senescence of renal tubular cells (RTCs) promotes the persistent progression of DN. Fatty-acid β‑oxidation (FAO) is the main energy source of RTCs; factors such as high glucose can trigger mitochondrial injury and abnormalities in renal tubular lipid metabolism, thereby constituting key contributors to stress-induced senescence of RTCs. Despite their ability to undergo cellular senescence, these cells maintain metabolic activity and continuously secrete pro-inflammatory, pro-fibrotic, and chemokine-related senescence-associated secretory phenotypes (SASP), which contribute to the sustained progression of DN. The mechanisms underlying lipid metabolism abnormalities in senescent RTCs are multifaceted. Dysregulation of the FABP, FATP, CD36, SREBP, CHREBP, PPARs, AMPK, CPT1, and HIF-1 pathways may result in persistent SASP factor secretion, increased fatty acid intake and synthesis, inhibition of FAO, and enhancement of glycolysis, which ultimately leads to stress-induced RTC senescence, renal fibrosis, and progression of DN. In addition to conventional hypoglycemic and lipid-lowering therapy, targeted intervention for these abnormal pathways and cellular changes is expected to improve RTC lipid metabolism abnormalities and stress-induced RTC senescence. In this review, we focused on the mechanisms underlying lipid metabolic dysfunction and stress-induced senescence in RTCs, summarizing and updating the latest therapeutic strategies for these conditions. Our study aims to provide a theoretical basis and novel insights for clinical interventions that target lipid-metabolic disturbances in senescent RTCs, improve stress-induced senescence, and delay the progression of DN.