International immunopharmacology · 2026
Gstk1 confers cardioprotection in sepsis by regulating mitochondrial function and inhibiting cGAS/STING-dependent inflammation and pyroptosis.
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Gao Min, Xu Changhao, Su Zhenyang, Kong Xiangqing, Xu Tianhua
Аннотация
BACKGROUND: Glutathione S-transferase kappa 1 (Gstk1) is known to be involved in antioxidant defense and mitochondrial function, yet its role in sepsis-induced myocardial injury (SMI) remains largely unexplored. This study aims to investigate the potential protective role of Gstk1 in LPS-induced myocardial injury and to elucidate its underlying mechanisms.
METHODS AND RESULTS: Using both in vivo and in vitro models of lipopolysaccharide (LPS)-induced myocardial injury, we found that cardiac-specific overexpression of Gstk1, achieved via viral delivery in mice, significantly improved cardiac function and structural integrity, attenuated the inflammatory response (IL-1β, IL-6, TNF-α), and suppressed pyroptosis (NLRP3, GSDMD-N, cleaved caspase-1). These in vivo findings were consistent with results from in vitro experiments. Conversely, Gstk1 knockdown exacerbated these detrimental effects. Mechanistically, Gstk1 overexpression improved mitochondrial function by restoring membrane potential, reducing superoxide production, increasing ATP levels, and inhibiting mitochondrial DNA (mtDNA) release. Further investigation revealed that Gstk1 exerts its protective effects by suppressing the cGAS/STING pathway.
CONCLUSION: Gstk1 plays a critical protective role in LPS-induced SMI by attenuating mitochondrial dysfunction, inhibiting inflammatory responses and pyroptosis, and modulating the cGAS/STING signaling pathway. These findings suggest Gstk1 as a potential therapeutic target for sepsis-related cardiac injury.
METHODS AND RESULTS: Using both in vivo and in vitro models of lipopolysaccharide (LPS)-induced myocardial injury, we found that cardiac-specific overexpression of Gstk1, achieved via viral delivery in mice, significantly improved cardiac function and structural integrity, attenuated the inflammatory response (IL-1β, IL-6, TNF-α), and suppressed pyroptosis (NLRP3, GSDMD-N, cleaved caspase-1). These in vivo findings were consistent with results from in vitro experiments. Conversely, Gstk1 knockdown exacerbated these detrimental effects. Mechanistically, Gstk1 overexpression improved mitochondrial function by restoring membrane potential, reducing superoxide production, increasing ATP levels, and inhibiting mitochondrial DNA (mtDNA) release. Further investigation revealed that Gstk1 exerts its protective effects by suppressing the cGAS/STING pathway.
CONCLUSION: Gstk1 plays a critical protective role in LPS-induced SMI by attenuating mitochondrial dysfunction, inhibiting inflammatory responses and pyroptosis, and modulating the cGAS/STING signaling pathway. These findings suggest Gstk1 as a potential therapeutic target for sepsis-related cardiac injury.