Fatty acid oxidation impairment in diabetic kidney disease: a bidirectional feedback network from mitochondrial quality control to systemic regulation
- 1Heilongjiang University of Chinese Medicine
Abstract
Diabetic kidney disease (DKD) is a major microvascular complication of diabetes with complex metabolic pathogenesis and limited therapeutic options. Defective fatty acid oxidation (FAO) and consequent lipotoxicity are central to renal fibrosis, but their systematic integration with other DKD pathologies remains incomplete. This Review examines the molecular links between FAO impairment and mitochondrial quality control, metabolic reprogramming, ferroptosis, ER stress, and gut dysbiosis. Based on current evidence, we propose that in diabetic kidney disease, defective fatty acid oxidation and impaired mitochondrial quality control form a self-amplifying bidirectional positive feedback loop. Hyperglycemia and lipotoxicity suppress PGC-1α-mediated mitochondrial biogenesis, promote excessive mitochondrial fission, and lead to impaired PINK1/Parkin-dependent mitophagy, thereby reducing fatty acid oxidation efficiency. The resulting ATP deficiency and lipid accumulation, in turn, elevate mitochondrial ROS levels and further exacerbate mitochondrial quality control dysregulation. This energy crisis then drives aberrant lipid accumulation, compensatory glycolytic enhancement, and blocked branched-chain amino acid catabolism, and amplifies injury signals through pathways such as ferroptosis and ER stress, ultimately establishing a systemic vicious cycle via the gut–kidney axis that promotes tubular injury and interstitial fibrosis. We also summarize emerging FAO-targeted interventions, including natural compounds, modern drugs, Chinese patent medicines, and lifestyle strategies. Although FAO impairment is now recognized as a key node in DKD progression, most evidence remains preclinical. Future integration of multi-omics and dynamic metabolic tracing is needed to establish causality and stage-specific roles, while dissecting the FAO regulatory architecture across renal cell types may offer new early diagnostic and therapeutic targets.
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BibTeX
@article{jiang2026fatty,
title = {{Fatty acid oxidation impairment in diabetic kidney disease: a bidirectional feedback network from mitochondrial quality control to systemic regulation}},
author = {Yuanxin Jiang and Wudi Zhang and Danmai Zhao and Zhe Chen and Zhonghong Yan},
journal = {Frontiers in Endocrinology},
year = {2026},
month = oct,
doi = {10.3389/fendo.2026.1968762},
url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1968762/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Fatty acid oxidation impairment in diabetic kidney disease: a bidirectional feedback network from mitochondrial quality control to systemic regulation
AU - Yuanxin Jiang
AU - Wudi Zhang
AU - Danmai Zhao
AU - Zhe Chen
AU - Zhonghong Yan
PY - 2026
DA - 2026/10/19
JO - Frontiers in Endocrinology
DO - 10.3389/fendo.2026.1968762
UR - https://www.frontiersin.org/articles/10.3389/fendo.2026.1968762/full
AB - Diabetic kidney disease (DKD) is a major microvascular complication of diabetes with complex metabolic pathogenesis and limited therapeutic options. Defective fatty acid oxidation (FAO) and consequent lipotoxicity are central to renal fibrosis, but their systematic integration with other DKD pathologies remains incomplete. This Review examines the molecular links between FAO impairment and mitochondrial quality control, metabolic reprogramming, ferroptosis, ER stress, and gut dysbiosis. Based on current evidence, we propose that in diabetic kidney disease, defective fatty acid oxidation and impaired mitochondrial quality control form a self-amplifying bidirectional positive feedback loop. Hyperglycemia and lipotoxicity suppress PGC-1α-mediated mitochondrial biogenesis, promote excessive mitochondrial fission, and lead to impaired PINK1/Parkin-dependent mitophagy, thereby reducing fatty acid oxidation efficiency. The resulting ATP deficiency and lipid accumulation, in turn, elevate mitochondrial ROS levels and further exacerbate mitochondrial quality control dysregulation. This energy crisis then drives aberrant lipid accumulation, compensatory glycolytic enhancement, and blocked branched-chain amino acid catabolism, and amplifies injury signals through pathways such as ferroptosis and ER stress, ultimately establishing a systemic vicious cycle via the gut–kidney axis that promotes tubular injury and interstitial fibrosis. We also summarize emerging FAO-targeted interventions, including natural compounds, modern drugs, Chinese patent medicines, and lifestyle strategies. Although FAO impairment is now recognized as a key node in DKD progression, most evidence remains preclinical. Future integration of multi-omics and dynamic metabolic tracing is needed to establish causality and stage-specific roles, while dissecting the FAO regulatory architecture across renal cell types may offer new early diagnostic and therapeutic targets.
SN - 1664-2392
ER -