Mitochondrial Fatty Acid Oxidation Dysfunction in Tubulointerstitial Fibrosis: Mechanisms and Therapeutic Advances

Tubulointerstitial fibrosis is a central pathological basis for the persistent progression of chronic kidney disease. Its initiation and progression involve multiple mechanisms, including disordered energy metabolism, lipid accumulation, inflammatory responses, and abnormal extracellular matrix deposition. As a major energy source for renal tubular epithelial cells, mitochondrial fatty acid oxidation (FAO) is essential for maintaining tubular metabolic homeostasis. Impaired FAO leads to insufficient ATP production, aggravated lipotoxicity, and mitochondrial homeostasis disruption, thereby further activating oxidative stress, inflammatory pathways, and profibrotic signaling, which, in turn, promote tubular injury and the progression of interstitial fibrosis. This review summarizes the basic physiological processes of mitochondrial FAO and its pathological role in tubulointerstitial fibrosis, with particular emphasis on the mechanisms by which FAO impairment drives metabolic reprogramming, lipotoxicity, and abnormalities in mitochondrial quality control. It also outlines recent advances in therapeutic strategies aimed at restoring FAO, improving mitochondrial function, and alleviating lipotoxicity and secondary profibrotic responses. Current evidence suggests that targeting FAO impairment may offer a promising therapeutic approach for delaying the progression of renal fibrosis; however, further efforts are needed to strengthen clinical translation.