2. Academic Validation
  3. Androgen receptor-NOX4-necroptosis axis drives male-biased susceptibility in aristolochic acid-induced acute kidney injury

Androgen receptor-NOX4-necroptosis axis drives male-biased susceptibility in aristolochic acid-induced acute kidney injury

  • Chem Biol Interact. 2026 Jun 1:432:112044. doi: 10.1016/j.cbi.2026.112044.
Haojie Wang 1,  Yu Wang 1,  Wenfei Lian 2,  Minbo Yan 1,  Junliang Qiu 1,  Zheyi Zhao 1,  Zhiwei Li 1,  Yong Wang 1,  Yashpal S Kanwar 3,  Yingbo Dai 4,  Xiaoping Zheng 5
Affiliations

Affiliations

  • 1 Department of Urology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China; Molecular Imaging Center, Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China.
  • 2 Department of Urology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China.
  • 3 Department of Pathology & Medicine, FSM, Northwestern University, Chicago, IL, USA. Electronic address: [email protected].
  • 4 Department of Urology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China; Molecular Imaging Center, Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China. Electronic address: [email protected].
  • 5 Department of Urology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China; Molecular Imaging Center, Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, China; Department of Pathology & Medicine, FSM, Northwestern University, Chicago, IL, USA; Department of Urology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, Hunan, China. Electronic address: [email protected].
PMID: 41864472 DOI: 10.1016/j.cbi.2026.112044
Abstract

Acute kidney injury (AKI) affects millions of patients worldwide and it is frequently caused by wide variety of nephrotoxins, including aristolochic acid I (AAI). Although sexual dimorphism is increasingly recognized in AKI, its mechanisms in AAI-induced injury remain unclear. In this study, using four sex-stratified AKI models-AAI nephrotoxicity, cisplatin nephrotoxicity, ischemia-reperfusion injury, and sepsis-associated AKI-we found that AAI-induced AKI displayed the most pronounced sexual dimorphism, with severe renal injury occurring predominantly in males. In HK-2 cells, AAI (100 μM) induced marked cytotoxicity and activation of the RIPK1/RIPK3/p-MLKL Necroptosis pathway, which was attenuated by the Necroptosis inhibitor Nec-1s (10 μM). In vivo, AAI (5 mg/kg/day, i. p. For 5 days) caused substantially greater tubular injury, renal dysfunction, and necroptotic activation in male mice than in females, whereas Nec-1s (1.65 mg/kg/day, i. p.) partially preserved renal structure and function. Mechanistically, integrated multi-omics, tissue analyses, and functional studies identified Androgen Receptor (AR) signaling as an upstream driver of male-biased injury. AR was enriched in proximal tubules and upregulated following AAI exposure, while pharmacologic AR blockade with bicalutamide restored cell viability in vitro (10 μM) and alleviated AAI-induced AKI in vivo (20 mg/kg, p. o., once daily), accompanied by suppression of necroptotic signaling. Further mechanistic studies demonstrated that AR transcriptionally activates NOX4, thereby increasing ROS generation and potentiating Necroptosis. Together, these findings define an AR-NOX4-necroptosis axis underlying male-biased vulnerability in acute AAI-induced AKI and implicate AR signaling and NOX4-driven oxidative stress as actionable therapeutic targets.

Keywords

Acute kidney injury; Androgen receptor; Aristolochic acid; Necroptosis; Sexual dimorphism.

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