Unlocking the gasotransmitter: hydrogen sulfide as a multitarget regulator in ischemia–reperfusion injury

Chen, Ye1; Deng, Yulin1; Tang, Rong1; Li, Shiqin1; Mei, Zhigang1,2,*; Ge, Jinwen1,3,*

Author Information

1Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan Province, China

2Academy of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha, Hunan Province, China

3Hunan Academy of Chinese Medicine, Changsha, Hunan Province, China

*Correspondence to: Jinwen Ge, PhD, 001267@hnucm.edu.cn; Zhigang Mei, PhD, meizhigang@hnucm.edu.cn

Funding:This work was supported from the National Natural Science Foundation of China (No. 82174167), the Key Project of Hunan Province Education Department (No. 20A366), the Project of Natural Science Foundation of Hunan Province (Nos. 2021JJ30499, 2025JJ90001), and the Young Qihuang Scholar Support Project of National Administration of Traditional Chinese Medicine (No. 2022).

Abstract

Ischemia–reperfusion injury, a critical pathophysiological phenomenon in multiple organ systems, remains a formidable therapeutic challenge in clinical practice. As the third endogenously produced gaseous signaling molecule, hydrogen sulfide (H2S) has emerged as a pivotal regulator of diverse physiological processes and pathological cascades. Accumulating evidence indicates that H2S exerts cytoprotective effects against cerebral, cardiac, hepatic, renal, and pulmonary ischemia–reperfusion injuries through multifaceted mechanisms involving mitigation of inflammatory responses, suppression of oxidative stress, modulation of autophagic processes, and inhibition of apoptotic pathways. This comprehensive review systematically examines the endogenous biosynthesis and metabolic regulation of H2S, while elucidating the molecular mechanisms underlying its organ protective effects during ischemia–reperfusion injury. Particular emphasis is placed on the therapeutic potential of H2S synthase isoforms and bioactive metabolites in ischemic pathophysiology. Notably, recent advances in H2S pharmacology have catalyzed the development of novel H2S donors and slow-releasing compounds, including HSDF-NH2, S-allyl cysteine, S-propargyl cysteine, and S-(4-fluorobenzyl)-N-(3,4,5-trimethoxybenzoyl)-L-cysteine. These pharmacological innovations demonstrate enhanced tissue specificity and controlled release kinetics, paving the way for clinical translation of H2S-based therapeutics in ischemia–reperfusion injury management. Future research directions should focus on optimizing drug delivery systems and elucidating the spatiotemporal dynamics of H2S signaling in organ-specific ischemia–reperfusion pathologies.

摘要

缺血再灌注损伤是多器官系统中一个关键的病理生理现象，在临床治疗中仍然是巨大的挑战。作为第三种内源性产生的气体信号分子，硫化氢已成为多种生理过程和病理级联反应的关键调节因子。越来越多的证据表明，硫化氢通过涉及减轻炎症反应、抑制氧化应激、调节自噬过程和抑制凋亡通路的多重机制，对脑、心、肝、肾和肺的缺血再灌注损伤发挥细胞保护作用。本综述系统性地审视了硫化氢的内源性生物合成与代谢调节，同时阐明了其在缺血再灌注损伤过程中发挥器官保护作用的分子机制。特别强调了硫化氢合酶亚型和生物活性代谢物在缺血性病理生理学中的治疗潜力。值得注意的是，硫化氢药理学的最新进展促进了新型硫化氢供体和缓释化合物的开发，包括HSDF-NH2、S-烯丙基半胱氨酸、S-炔丙基半胱氨酸和S-(4-氟苄基)-N-(3,4,5-三甲氧基苯甲酰基)-L-半胱氨酸。这些药理学创新展现出更强的组织特异性和可控的释放动力学，为基于硫化氢的疗法在缺血再灌注损伤管理中的临床转化铺平了道路。未来的研究方向应聚焦于优化递药系统，并阐明器官特异性缺血再灌注病理过程中硫化氢信号的时空动态变化。