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HIF-1α mediates mitochondrial damage by down-regulating ALKBH7 expression to promote the aberrant activation of FLS in rheumatoid arthritis

Acta Pharmacologica Sinica volume 46, pages 2225–2236 (2025)Cite this article

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation and progressive joint destruction. Existing evidence indicates that hypoxia potentially contributes to the pathology of RA, though the specific mechanism remains unidentified. In this study, we explored the molecular mechanism through which the hypoxia-inducible factor (HIF-1α) contributed to the pathological process of RA. Our preliminary results suggested that hypoxia stimulates the activation of fibroblast-like synoviocytes (FLS) by inducing mitochondrial damage to activate cGAS-STING signaling, which can be effectively inhibited by silencing HIF-1α. In line with this, HIF-1α deficiency significantly alleviated the symptoms of collagen-induced arthritis (CIA) mice. RNA-Seq and CUT-Tag analysis revealed that HIF-1α down-regulated the expression of AlkB homologue 7 (ALKBH7) by acting on the ALKBH7 promoter site on chromosome 19 6372400-6372578. Using dual luciferase reporter analysis, we identified that ACCGTGGC as the motif to which HIF-1α bound directly. Subsequently, we demonstrated that knockdown of ALKBH7 induces mitochondrial damage and activates cGAS-STING signaling by downregulating the expression of UQCRC2. Conversely, overexpression of ALKBH7 could resist hypoxia-induced mitochondrial damage and FLS activation. In conclusion, HIF-1α triggers mitochondrial damage by downregulating the expression of ALKBH7 thereby promoting FLS activation, which may be the molecular mechanism by which hypoxia is involved in the pathological process of RA.

Hypoxia promotes the activation of FLS through the induction of mitochondrial damage, which subsequently activates cGAS-STING signaling. Mechanistically, HIF-1α triggers mitochondrial damage by downregulating the expression of ALKBH7 in a target manner. Furthermore, the deletion of ALKBH7 leads to mitochondrial damage under hypoxic conditions, primarily through the downregulation of UQCRC2, as opposed to other complexes.

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Fig. 1: Hypoxia, mitochondrial damage, and abnormal activation of cGAS-STING signaling were present in FLS of RA patients.
Fig. 2: Hypoxia induces mitochondrial damage and cGAS-STING signaling activation in FLS.
Fig. 3: Silencing HIF-1α inhibits mitochondrial damage and cGAS-STING signaling activation in FLS induced by hypoxia.
Fig. 4: HIF-1α deficiency improved symptoms of RA in CIA mice.
Fig. 5: HIF-1α target downregulation of ALKBH7 expression.
Fig. 6: Low level of ALKBH7 promotes the aberrant activation of FLS by downregulating UQCRC2 expression.

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Acknowledgements

We acknowledge the technical support provided by Weihuan Biotechnology Co., Ltd. The research was funded by the National Natural Science Foundation of China (82204403 and 82373878), The Major Projects of the Anhui Provincial Department of Education (2023AH040080), the Anhui Provincial Natural Science Foundation (2308085MH312), and the Postgraduate Innovation Research and Practice Program of Anhui Medical University (YJS20230009).

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  1. These authors contributed equally: Han Wang, Yu-chen Zhao, Li Xu, Tian-jing Zhang

Authors and Affiliations

  1. Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, China

    Han Wang, Yu-chen Zhao, Li Xu, Tian-jing Zhang, Liang-hu Liu, Meng-qi Zhou, Han Zhang, Yin-ning Yang, Lin Jin, Zi-wei Zhang, Xian-zheng Zhang & Ling-ling Zhang

  2. Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, 230032, China

    Han Wang, Yu-chen Zhao, Li Xu, Tian-jing Zhang, Liang-hu Liu, Meng-qi Zhou, Han Zhang, Yin-ning Yang, Lin Jin, Zi-wei Zhang, Xian-zheng Zhang & Ling-ling Zhang

  3. Anti-inflammatory Immune Drugs Collaborative Innovation Center, Anhui Province, Hefei, 230032, China

    Han Wang, Yu-chen Zhao, Li Xu, Tian-jing Zhang, Liang-hu Liu, Meng-qi Zhou, Han Zhang, Yin-ning Yang, Lin Jin, Zi-wei Zhang, Xian-zheng Zhang & Ling-ling Zhang

  4. The Second People’s Hospital of Hefei, Hefei, 230011, China

    Pin Pan

  5. Department of Oncology, The First Affiliated Hospital, Institute for Liver Diseases of Anhui Medical University, Hefei, 230032, China

    Xian-zheng Zhang

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Contributions

The majority of experiments, data analysis, and manuscript composition were conducted by HW, YCZ and LX. Synovial tissue from OA patients, as well as RA patients undergoing joint replacement, was provided by PP with the patients’ consent for the purposes of this study. Additional experiments were carried out by TJZ, LHL, MQZ, HZ, and YNY. The manuscript and figures underwent significant revisions and improvements under the guidance of LJ and ZWZ. XZZ and Pro. LLZ contributed their expertise to the experimental design, data processing, and manuscript writing. The final manuscript has been thoroughly reviewed and approved by all authors.

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Correspondence to Xian-zheng Zhang or Ling-ling Zhang.

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Wang, H., Zhao, Yc., Xu, L. et al. HIF-1α mediates mitochondrial damage by down-regulating ALKBH7 expression to promote the aberrant activation of FLS in rheumatoid arthritis. Acta Pharmacol Sin 46, 2225–2236 (2025). https://doi.org/10.1038/s41401-025-01520-y

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