胱硫醚γ裂解酶 (CSE) 和 TNF-α 现在被认为是肠道稳态、炎症和伤口愈合的关键调节因子。在结肠上皮细胞中，这两种分子已被证明可以影响多种生物过程，但 CSE 和 TNF-α 调节的细胞内信号通路之间的具体相互作用尚不清楚。在本研究中，我们在体外分析和功能测定中使用 CSE 特异性药理学抑制剂和 siRNA 介导的瞬时基因沉默，研究了正常结肠细胞和健康人结肠的类器官模型中的这些相互作用。我们证明 CSE 和 TNF-α 在结肠上皮细胞中相互调节彼此的功能。 TNF-α 处理可在几分钟内刺激 CSE 活性，并在 24 小时后上调 CSE 表达，增加内源性 CSE 衍生的 H2S 产量。反过来，CSE 活性促进 TNF-α 诱导的 NF-κB 和 ERK1/2 激活，但不影响 p38 MAPK 信号通路。抑制 CSE 活性可以完全消除 TNF-α 诱导的跨上皮通透性和伤口愈合的增加。我们的数据表明，CSE 活性可能对于有效的 TNF-α 介导的肠道损伤反应至关重要。此外，CSE 对 TNF-α 控制的细胞内信号通路的调节可以为与上皮伤口愈合受损相关的结肠疾病提供新的治疗靶点。

Cystathionine gamma-lyase (CSE) and TNF-α are now recognized as key regulators of intestinal homeostasis, inflammation, and wound healing. In colonic epithelial cells, both molecules have been shown to influence a variety of biological processes, but the specific interactions between intracellular signaling pathways regulated by CSE and TNF-α are poorly understood. In the present study, we investigated these interactions in normal colonocytes and an organoid model of the healthy human colon using CSE-specific pharmacological inhibitors and siRNA-mediated transient gene silencing in analytical and functional assays in vitro. We demonstrated that CSE and TNF-α mutually regulated each other's functions in colonic epithelial cells. TNF-α treatment stimulated CSE activity within minutes and upregulated CSE expression after 24 h, increasing endogenous CSE-derived H2S production. In turn, CSE activity promoted TNF-α-induced NF-ĸB and ERK1/2 activation but did not affect the p38 MAPK signaling pathway. Inhibition of CSE activity completely abolished the TNF-α-induced increase in transepithelial permeability and wound healing. Our data suggest that CSE activity may be essential for effective TNF-α-mediated intestinal injury response. Furthermore, CSE regulation of TNF-α-controlled intracellular signaling pathways could provide new therapeutic targets in diseases of the colon associated with impaired epithelial wound healing.