{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Cystathionine γ‐lyase (CTH)—often referred to as cystathionine‐γ‐lyase or CSE—is a key enzyme of the transsulfuration pathway that catalyzes the conversion of L‐cysteine (and, under some conditions, homocysteine) into hydrogen sulfide (H₂S) and other sulfur metabolites. This endogenous gaseous mediator plays a multifaceted role in cellular signaling by modulating redox homeostasis, inflammation, metabolism, vascular tone, cellular proliferation, and apoptosis.\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n At the biochemical level, detailed kinetic analyses have delineated a range of H₂S‐producing reactions catalyzed by CTH, with significant implications for maintaining cellular antioxidant capacity and proper homocysteine management."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In several cell types, H₂S generated by CTH exerts cytoprotective effects through antioxidant and anti‐apoptotic signaling, in part via sulfhydration of key regulatory proteins such as protein tyrosine phosphatases."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the cardiovascular system, CTH‐derived H₂S has been shown to protect against ischemic injury and heart failure by preserving mitochondrial function, up‐regulating endothelial nitric oxide synthase activity, and activating cardioprotective kinase cascades. For example, cardiac‐specific overexpression of CTH improves outcomes in models of pressure overload and cardiac arrest"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "and"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", respectively.\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the nervous system, decreased CTH expression is associated with neurodegenerative conditions such as Huntington’s disease, suggesting that loss of CTH‐derived H₂S may exacerbate oxidative stress and neurotoxicity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Similarly, in vascular smooth muscle cells, overexpression of CTH can modulate cell growth and apoptosis via downstream regulators (e.g. ERK, p21, cyclin D1), highlighting a role in vascular remodeling and blood pressure regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In reproductive biology, CTH‐mediated H₂S production supports placental vasculature and trophoblast function; inhibition of CTH activity is linked to reduced placental growth factor production, impaired trophoblast invasion, and features of preeclampsia"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Endogenous H₂S also plays an important role in metabolic regulation. For instance, vitamin D has been shown to stimulate CTH activity, thereby enhancing GLUT4 translocation and glucose utilization in adipocytes, which may have implications for glucose homeostasis in diabetes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " In addition, CTH activity modulates renovascular remodeling in diabetic kidneys by affecting key signaling pathways, including NMDA receptor and connexin expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In cancer, the function of CTH appears to be context dependent. In some tumor types, such as colon cancer, Wnt‐mediated up‐regulation of CTH supports bioenergetics, angiogenesis, and cell proliferation, contributing to tumor growth and chemoresistance"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", whereas in other contexts (e.g. melanoma), increased CTH expression can promote apoptosis of tumor cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, genetic and nutritional studies underscore the systemic importance of CTH. Mice with targeted deletion of the CTH gene exhibit reduced cysteine, glutathione, and H₂S production, leading to oxidative stress and eventual lethality under cysteine‐limited conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " In humans, mutations in the CTH gene cause cystathioninuria, a disorder that manifests due to impaired conversion of methionine into cysteine"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", while studies in liver models indicate that adequate CTH function is critical to detoxify excess methionine and its potentially toxic metabolites."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, CTH is pivotal for H₂S production and the maintenance of cellular redox and metabolic homeostasis. Its diverse functions span cardioprotection, vascular regulation, metabolic control, neuroprotection, and the modulation of tumor biology. Owing to its broad involvement in these physiological and pathophysiological processes, CTH represents a promising therapeutic target in diseases such as heart failure, diabetes, neurodegeneration, preeclampsia, and cancer.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Taurai Chiku, Dominique Padovani, Weidong Zhu, et al. 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