Volume 281, May 2026, 156384Author links open overlay panelJingcong Huang 1, Minyu Shi 1, Ziqing Zhang, Zhenyu Xu, Xixiang XiShow moreAbstract

Sepsis-associated acute kidney injury (SA-AKI) is a major contributor to mortality in sepsis; however, its pathological mechanism remains elusive. The objective of this study is to explore the regulatory role and underlying mechanisms of the cytokine-induced apoptosis inhibitor 1 (CIAPIN1)-optic atrophy 1 (OPA1) signaling axis in SA-AKI. Lipopolysaccharide (LPS)-stimulated HK-2 cells were employed to assess the roles of CIAPIN1 and OPA1 in regulating cell apoptosis, mitochondrial damage, and inflammatory responses via loss- and gain-of-function experiments. The functional interaction between CIAPIN1 and OPA1 was investigated. The impact of N6-methyladenosine (m6A) modification on LPS-induced alterations in CIAPIN1 expression was further examined. In vivo, a murine AKI model was established to evaluate the effect of Ciapin1 silencing on renal tissue injury, mitochondrial dysfunction, and inflammation. Overexpression of CIAPIN1 significantly attenuated cell apoptosis, enhanced mitochondrial membrane potential, and restored the expression of mitochondrial function-related proteins while suppressing the release of inflammatory factors in LPS-stimulated HK-2 cells. OPA1 overexpression rescued the detrimental effects of CIAPIN1 knockdown on cell apoptosis, mitochondrial dysfunction, and inflammation in HK-2 cells. Wilms' tumor 1-associating protein (WTAP) promotes m6A modification of CIAPIN1 mRNA. Ciapin1 knockdown exacerbated renal tissue injury, apoptosis, mitochondrial damage, and inflammation in a murine AKI model induced by cecal ligation and puncture. This study uncovers the CIAPIN1-OPA1 signaling axis as a novel mechanistic basis for SA-AKI, wherein it regulates mitochondrial function, inflammatory response, and cellular apoptosis in renal tissues under septic stress.

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Access through your organizationSection snippetsBackground

Sepsis, a life-threatening syndrome triggered by dysregulated host responses to infection, leads to organ dysfunction [1]. The kidneys represent primary target organs in this process, frequently developing sepsis-associated acute kidney injury (SA-AKI) —a key factor driving sepsis-related mortality [2]. SA-AKI occurs in nearly 50 % of sepsis patients and more than doubles the mortality risk [3]. Current clinical and research evidence indicates that SA-AKI pathogenesis involves multiple

Cell and culture

Human renal epithelial cells HK-2 (American Type Culture Collection) were maintained in DMEM/F12 medium containing 10 % fetal bovine serum, 0.1 mg/mL streptomycin, and 100 U/mL penicillin. Cells at 80–90 % confluence were exposed to 10 μg/mL LPS. Following 24 hrs of LPS stimulation, cells were harvested for subsequent analysis.

Plasmid construction and viral transduction

CIAPIN1-targeting short hairpin RNAs (shCIAPIN1–1, shCIAPIN1–2, shCIAPIN1–3) were cloned into the pLKO.1 vector. For gain-of-function studies, the full-length CIAPIN1 or

CIAPIN1 overexpression alleviates cell apoptosis, inflammation, and mitochondrial damage in HK-2 cells induced by LPS

CIAPIN1 expression decreased progressively with LPS treatment duration (Fig. 1A-C). To investigate CIAPIN1's role in LPS-induced injury, HK-2 cells were transduced with a CIAPIN1 expression vector (Fig. 1D-F), followed by 24-hour LPS exposure. Analysis of cell survival revealed that CIAPIN1 overexpression protected HK-2 cells against LPS-induced injury compared with LPS-treated controls (Fig. 1G) and reduced the apoptotic cell percentage (Fig. 1H). Analysis of inflammasome activation-related

Discussion

Research on the molecular pathological mechanisms of SA-AKI provides the foundation for translating findings into potential therapeutic strategies and for the development and testing of promising pharmacological approaches in clinical trials [20]. This study demonstrates that CIAPIN1 expression is downregulated under LPS stress and CIAPIN1 functions as a critical protective mediator in LPS-induced HK-2 cell damage and CLP-induced AKI by inhibiting apoptosis, preserving mitochondrial integrity,

Conclusions

In conclusion, CIAPIN1, governed by WTAP-mediated m6A modification, emerges as a master regulator of mitochondrial quality control and inflammation in AKI, operating largely through OPA1. Mitochondrial dynamics (via OPA1), epigenetic transcriptional regulation (via WTAP-m6A-CIAPIN1), and inflammatory signaling, suggesting combined targeting of this axis may synergistically protect kidneys. Enhancing this pathway represents a promising strategy for clinical SA-AKI intervention.

CRediT authorship contribution statement

Xixiang Xi: Writing – review & editing, Supervision. Zhenyu Xu: Writing – original draft, Supervision, Methodology, Investigation, Formal analysis. Ziqing Zhang: Methodology, Investigation, Formal analysis. Minyu Shi: Writing – review & editing, Methodology, Conceptualization. Jingcong Huang: Writing – original draft, Conceptualization.

Patient consent for publication

Not applicable.

Ethics approval

All animal procedures were approved by the Institutional Animal Care and Use Committee of the Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine (Approval number 2024-AR-025).

Funding

This study was supported by the Key Specialty Construction Project of Pudong Health and Family Planning Commission of Shanghai (PWZzk 2022–15) and Pudong New Area Famous Traditional Chinese Medicine Inheritors Training Program 2025 (PDZY-2025–0946).

Declaration of Competing Interest

The authors declare that they have no competing interests.

Acknowledgments

Not applicable.

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