Cystathionine γ-lyase downregulation promotes liver injury and necroptosis through reprogramming of methionine cycle.

ABSTRACT:

Objective

Chronic liver diseases (CLDs) are prevalent globally. The purpose of the current study was to elucidate the regulatory mechanisms underlying the pathophysiological processes in CLDs.

Methods and results

Using the GEO database, we identified cysteine and methionine metabolism as a commonly enriched pathway in some CLDs. We then confirmed that hepatic cystathionine γ-lyase (Cth), a key enzyme in this pathway, was significantly downregulated in some CLDs in humans and rodent models. Cth-deficient mice exhibited hepatic necroptosis, inflammation and mitochondrial impairment. Omics revealed methionine cycle dysregulation and reduced betaine, a methionine cycle metabolite. Betaine supplementation rewired the methionine cycle, and alleviated necroptosis, inf

SUBMITTER: Wu C 

PROVIDER: S-EPMC12305881 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature