Attenuation of arsenic trioxide‐induced endothelial injury: unveiling the protective role of ginkgolic acid through inhibition of TRPM4 SUMOylation: Evidence from Raman cellular imaging

作者：Ting‐Ting Tong, Yadong Xue, Yuyao Zhang, Chunxiao Yu, Xin‐Yu Yao, Yu‐Xuan Han, Kai Zhang, Mei‐Mei Shen, Yu Zhao, Yunfeng Cui, Ziyue Ma, Yuyang Fu, Yongzhen Wang, Jing Jin, Ke Tang, Yang Liu, Yang Li, Rong Huo, Tao Ban · 发表于：Open Research (University of Surrey) · 年份：2025 · DOI：10.1002/viw.20250049 · 被引用次数：2 · 研究领域：Ion Channels and Receptors、Curcumin's Biomedical Applications、Retinoids in leukemia and cellular processes

Abstract Arsenic trioxide (ATO) therapy is limited by its severe vascular toxicity, which manifests as endothelial injury through mechanisms that remain poorly defined. This study identifies the SUMOylation of the Transient Receptor Potential Melastatin 4 (TRPM4) channel as a pivotal pathological driver of this process. We demonstrate that the SUMOylation inhibitor ginkgolic acid (GA) confers protection by attenuating ATO‐induced TRPM4 overactivation, thereby rescuing endothelial cells from ionic dysregulation (Ca 2 ⁺, Na⁺), oxidative stress, membrane depolarization, and apoptosis. Critically, we identified lysine 618 (K618) as the key SUMOylation site on TRPM4. Expression of a SUMOylation‐deficient TRPM4 mutant (K618R) phenocopied the protective effects of GA, significantly mitigating ATO‐induced endothelial dysfunction. This confirms that the detrimental effects of TRPM4 are strictly dependent on its SUMOylation at this residue. The protective efficacy of GA was further validated ex vivo, where it restored endothelium‐dependent vasodilation in rat mesenteric arteries impaired by ATO. Complementing these findings, Raman microimaging provided unique, label‐free insights into the biochemical alterations induced by ATO and their reversal by GA at the single‐cell level. Our findings unveil TRPM4‐SUMOylation at K618 as a fundamental mechanism underlying ATO‐induced endothelial injury. These results position the inhibition of this specific post‐translational modification as a prom...