The Lipid-Oxidative Stress Axis: Novel Therapeutic Targets for Podocytopathy.

Abstract

Podocytes, as terminally differentiated cells within the glomerulus, play a decisive role in maintaining the molecular selectivity of the glomerular filtration barrier (GFB) through structural integrity and functional homeostasis. Podocyte injury not only directly compromises GFB integrity but also serves as a central pathological mechanism underlying the progression of proteinuric nephropathy. Evidence from studies highlights an intricate link between lipid metabolism dysregulation and podocyte dysfunction: Renal ectopic lipid accumulation (ELA) disrupts intracellular homeostasis via lipotoxic effects, inducing mitochondrial oxidative stress, cytoskeletal remodeling, and inflammatory cascades. Concurrently, excessive reactive oxygen species (ROS) generation coupled with compromised antioxidant defense mechanisms establishes a self-perpetuating cycle of redox imbalance. This bidirectional crosstalk within the lipid-oxidative stress axis triggers irreversible pathological alterations. This review summarizes the effects of abnormal signals during lipid synthesis, breakdown, and metabolism on podocytes, as well as the interaction between mitochondria and podocyte dysfunction through signaling mechanisms in lipid metabolism disorders. We also sorted out the key molecular pathways involved in this axis, and the regulation of key nodes of lipid metabolism (SREBP pathway, HMGCR pathway), improvement of mitochondrial function (mitochondrial dynamics and energy metabolism), and activation of antioxidant defenses (AMPK pathway) are highly promising therapeutic targets for intervening in podocyte damage and blocking the progression of the disease.