Mitophagy Pathways and Therapeutic Applications in Renal Fibrosis

² Research Center of Intergated Traditional Chinese and Western Medicine, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, Sichuan, China,

³ Department of Nephrology, Affiliated Hospital, Southwest Medical University, Luzhou 646000, Sichuan, China; Department of Nephrology, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou 646000, Sichuan, China,

JCNR 2026 , 10(2), 312–335; https://doi.org/10.26689/jcnr.v10i2.14098

© 2026 by the Authors. Licensee Whioce Publishing, Singapore. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )

Abstract

Chronic kidney disease (CKD), a global health burden, progresses through renal fibrosis driven by mitochondrial dysfunction in metabolically active renal cells. As the kidney harbors exceptionally high mitochondrial density, defective mitophagy, a quality control mechanism for clearing damaged mitochondria have emerged as a central pathological trigger. Environmental toxins, such as perfluorinated compounds, disrupt lysosomal-mitochondrial crosstalk, exacerbating fibrotic pathways via metabolic reprogramming and sustained activation of pro-fibrotic signaling axes like FGF9/PI3K/Akt. Impaired PINK1/Parkin-mediated mitophagy permits accumulation of fragmented mitochondria, fueling oxidative stress and TGF-β/Smad3-driven epithelial-mesenchymal transition (EMT) and fibroblast activation. Recent therapeutic advances focus on restoring mitophagic flux to counteract fibrosis. Small-molecule activators (UMI-77) enhance mitochondrial clearance, attenuating NF-κB-mediated inflammation and collagen deposition. Nanotechnology-augmented mesenchymal stem cells offer targeted delivery of mitophagy modulators to damaged tubules, synergizing mitochondrial repair with anti-inflammatory effects. While preclinical studies highlight promising agents like SS-31 and MitoQ, challenges persist in achieving tissue-specific mitochondrial targeting and ensuring long-term genomic safety. This review synthesizes molecular insights into mitophagy dysregulation in fibrosis, explores innovative intervention strategies, and underscores the need for multi-omics approaches to optimize mitochondrial therapeutics. Bridging translational gaps through advanced delivery systems and patient-specific mitochondrial profiling may unlock precision therapies for halting CKD progression.

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