Impact of renal lipid droplet dynamics on tubular health.

Lipid droplets (LDs) are dynamic organelles that regulate lipid storage, metabolism, and organelle crosstalk. In renal tubular cells, which rely heavily on fatty acid oxidation for energy, LDs play a dual role. The transient accumulation of LDs during acute stress may protect against excess fatty acid accumulation and reduce lipotoxicity, but persistent LD overload contributes to mitochondrial dysfunction, oxidative stress, inflammation, and fibrotic remodeling. This review synthesizes recent advances in LD biology in the kidney, highlighting mechanisms of biogenesis, turnover via lipolysis and lipophagy, and interactions of LDs with mitochondria, the endoplasmic reticulum, and peroxisomes. We compare adaptive versus maladaptive LD-mediated responses across acute kidney injury, chronic kidney disease, and diabetic nephropathy, integrating evidence from human biopsies, animal models, and in vitro studies. Preclinical studies indicate that restoring fatty acid oxidation and improving lipid turnover can reduce tubular injury and fibrosis. However, the effects of directly suppressing LD formation are context dependent because transient neutral-lipid storage may protect cells from excess free fatty acids, whereas persistent LD accumulation can accompany lipotoxic injury. Clinically, PPAR agonists, SGLT2 inhibitors, and GLP-1 receptor agonists improve selected renal outcomes, but direct evidence that they reduce tubular LD burden in humans is lacking. However, kidney-specific biomarkers and drug delivery strategies remain underdeveloped. Key research gaps include a complete understanding of nephron segment-specific LD biology, LD heterogeneity, organelle crosstalk, and sex- and age-related regulation of LDs. Advances in patient-derived organoids, tubuloids, and kidney-on-a-chip models provide new opportunities to evaluate LD dynamics and identify targeted interventions. With these tools, the understanding of LD biology and pathophysiology will increase, and LDs may become a therapeutic target for protecting tubular health and slowing the progression of kidney disease.