Zishen Huoxue decoction(ZSHX)enhances cardiomyocyte viability following hypoxic stress;however,its upstream therapeutic targets remain unclear.Network pharmacology and RNA sequencing analyses revealed that ZSHX target...Zishen Huoxue decoction(ZSHX)enhances cardiomyocyte viability following hypoxic stress;however,its upstream therapeutic targets remain unclear.Network pharmacology and RNA sequencing analyses revealed that ZSHX target genes were closely associated with mitophagy and apoptosis in the mitochondrial pathway.In vitro,ZSHX inhibited pathological mitochondrial fission following hypoxic stress,regulated FUN14 domain-containing protein 1(FUNDC1)-related mitophagy,and increased the levels of mitophagy lysosomes and microtubule-associated protein 1 light chain 3 beta II(LC3II)/translocase of outer mitochondrial membrane 20(TOM20)expression while inhibiting the over-activated mitochondrial unfolded protein response.Additionally,ZSHX regulated the stability of beta-tubulin through Sirtuin 5(SIRT5)and could modulate FUNDC1-related synergistic mechanisms of mitophagy and unfolded protein response in the mitochondria(UPR^(mt))via the SIRT5 and-β-tubulin axis.This targeting pathway may be crucial for cardiomyocytes to resist hypoxia.Collectively,these findings suggest that ZSHX can protect against cardiomyocyte injury via the SIRT5-β-tubulin axis,which may be associated with the synergistic protective mechanism of SIRT5-β-tubulin axis-related mitophagy and UPR^(mt) on cardiomyocytes.展开更多
基金supported by the National Natural Science Foundation of China(No.82305204),the Special Project on Academic Inheritance and Communication,China Academy of Chinese Medical Sciences(No.CI2022E012XB)Chinese Academy of Chinese Medical Sciences Doctoral Talents Training Fund(No.2021)+1 种基金the Special Program for Training Outstanding Young Talents of Chinese Academy of Traditional Chinese Medicine(No.ZZ16-YQ-021)the Innovative Cultivation Project of Guang'anmen Hospital,Chinese Academy of Chinese Medical Sciences(No.2022s481).
文摘Zishen Huoxue decoction(ZSHX)enhances cardiomyocyte viability following hypoxic stress;however,its upstream therapeutic targets remain unclear.Network pharmacology and RNA sequencing analyses revealed that ZSHX target genes were closely associated with mitophagy and apoptosis in the mitochondrial pathway.In vitro,ZSHX inhibited pathological mitochondrial fission following hypoxic stress,regulated FUN14 domain-containing protein 1(FUNDC1)-related mitophagy,and increased the levels of mitophagy lysosomes and microtubule-associated protein 1 light chain 3 beta II(LC3II)/translocase of outer mitochondrial membrane 20(TOM20)expression while inhibiting the over-activated mitochondrial unfolded protein response.Additionally,ZSHX regulated the stability of beta-tubulin through Sirtuin 5(SIRT5)and could modulate FUNDC1-related synergistic mechanisms of mitophagy and unfolded protein response in the mitochondria(UPR^(mt))via the SIRT5 and-β-tubulin axis.This targeting pathway may be crucial for cardiomyocytes to resist hypoxia.Collectively,these findings suggest that ZSHX can protect against cardiomyocyte injury via the SIRT5-β-tubulin axis,which may be associated with the synergistic protective mechanism of SIRT5-β-tubulin axis-related mitophagy and UPR^(mt) on cardiomyocytes.
