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

Abstract

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.

Keywords

Tubulointerstitial fibrosis / Fatty acid oxidation / Mitochondrial dysfunction / Lipotoxicity / Chronic kidney disease

Statement of the Use of Generative AI and AI-Assisted Technologies in the Writing Process

During the preparation of this manuscript, the authors utilized the generative AI tool ChatGPT to refine the language of the entire text, aiming to enhance the fluency of English expression and adherence to academic standards. The AI tool was not involved in the study design, the derivation of conclusions, or the creation of figures, tables, and references. All text generated or modified by the AI has been carefully reviewed, revised, and approved by the authors sentence by sentence. The authors assume full responsibility for the final content of the published article.

Acknowledgments

We thank the Hub Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province for providing technical and platform support for this study.

Author Contributions

Conceptualization, J.F. and W.Z.; Writing-Original Draft Preparation, S.L.; Writing-Review & Editing, J.F. and J.Z.; Supervision, J.Z. and W.Z.; Project Administration, J.Z. and W.Z.

Ethics Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No data were generated or analyzed in this review.

Funding

This study was supported by the National Natural Science Foundation of China (grant number 82400854; 82500910); China Postdoctoral Science Foundation (grant number 2024M763008); and the Henan Provincial Medical Science and Technology Research Project (grant number LHGJ20240189).

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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