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<p>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.</p><p></p>

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

  • 期刊论文

  • 发表日期：

    2025年3月26日

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

摘要

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.