2. Academic Validation
  3. cGAS-STING signaling pathway promotes ischemic kidney injury by regulating HK3-mediated lipid accumulation

cGAS-STING signaling pathway promotes ischemic kidney injury by regulating HK3-mediated lipid accumulation

  • Free Radic Biol Med. 2026 Jun:249:246-259. doi: 10.1016/j.freeradbiomed.2026.03.036.
Dongyun Wang 1,  Zihui Zhou 2,  Zhibo Zhao 3,  Mengyu Liu 4,  Yue Li 5,  Lin Mu 6,  Huandi Zhou 7,  Xinran Li 8,  Fang Zhang 9,  Shuangshuang Tian 10,  Xiaoshuang Zhou 11,  Yonghong Shi 12
Affiliations

Affiliations

  • 1 Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, China; Shanxi Provincial Key Laboratory of Kidney Disease, Shanxi Provincial People's Hospital, Taiyuan, 030012, China. Electronic address: [email protected].
  • 2 Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, China; Hebei Key Laboratory of Kidney Disease, Shijiazhuang, 050017, China. Electronic address: [email protected].
  • 3 Shanxi Provincial Key Laboratory of Kidney Disease, Shanxi Provincial People's Hospital, Taiyuan, 030012, China. Electronic address: [email protected].
  • 4 Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, China. Electronic address: [email protected].
  • 5 Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, China. Electronic address: [email protected].
  • 6 Hebei Key Laboratory of Kidney Disease, Shijiazhuang, 050017, China; Department of Nephrology, Second Hospital of Hebei Medical University, Shijiazhuang, 050051, China. Electronic address: [email protected].
  • 7 Department of Nephrology, Second Hospital of Hebei Medical University, Shijiazhuang, 050051, China. Electronic address: [email protected].
  • 8 Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, China. Electronic address: [email protected].
  • 9 Shanxi Provincial Key Laboratory of Kidney Disease, Shanxi Provincial People's Hospital, Taiyuan, 030012, China. Electronic address: [email protected].
  • 10 Shanxi Provincial Key Laboratory of Kidney Disease, Shanxi Provincial People's Hospital, Taiyuan, 030012, China. Electronic address: [email protected].
  • 11 Shanxi Provincial Key Laboratory of Kidney Disease, Shanxi Provincial People's Hospital, Taiyuan, 030012, China. Electronic address: [email protected].
  • 12 Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, China; Hebei Key Laboratory of Kidney Disease, Shijiazhuang, 050017, China. Electronic address: [email protected].
PMID: 41825654 DOI: 10.1016/j.freeradbiomed.2026.03.036
Abstract

Lipid accumulation and chronic inflammation are key drivers of chronic kidney disease (CKD) progression to renal fibrosis, but the underlying mechanisms remain incompletely understood. The stimulator of interferon genes (STING), a central regulator of innate immunity and inflammatory responses, has recently garnered significant attention in the context of kidney disease. In this study, we demonstrate that STING expression is markedly upregulated in fibrotic kidneys from both CKD patients and mice subjected to ischemia-reperfusion injury (IRI). Genetic ablation or pharmacological inhibition of STING alleviated renal fibrosis, inflammation, and lipid accumulation in IRI mice, effects that were closely associated with Hexokinase 3 (HK3)-mediated lipid metabolism. Moreover, inhibition of STING suppressed NF-κB activation and subsequently reduced HK3 upregulation, thereby attenuating hypoxia/reoxygenation-induced fibrosis, inflammation, and lipid accumulation in primary mouse renal tubular cells (RTECs) and HK-2 cells. Mechanistically, activation of the cGAS-STING signaling pathway promotes the binding of its downstream effector NF-κB p65 to the HK3 promoter, which initiates transcriptional upregulation of HK3, leading to dysregulated lipid metabolism, enhanced inflammation, and ultimately renal fibrosis. Taken together, our findings indicate that the cGAS-STING-NF-κB-HK3 signaling axis may represent a novel therapeutic target for early-stage renal fibrosis.

Keywords

Hexokinase 3; Kidney fibrosis; Lipid accumulation; cGAS-STING signaling pathway.

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