Regulatory CD4+ T cells (Tregs) are critical for maintaining tolerance to self. Chronic inflammation can cause Treg instability which is defined by loss of CD25 and the lineage-defining transcription factor FOXP3, resulting in exTreg cells.
To better understand the factors driving Treg to exTreg conversion, we analyzed transcriptomes of Treg subsets expressing varied levels of CD25 and FOXP3 in human peripheral blood CD4+ T cells.
We found differential expression of genes related to inflammatory signaling (IFNG, TNF), cytotoxicity (PRF1, GZMB) and cellular stress (HSPA5). This was confirmed at the protein level by flow cytometry. Distinct Treg populations were also defined by unique metabolic profiles suggesting a role of cell-intrinsic metabolic programs in maintaining Treg stability.
Our findings start to define novel cellular pathways contributing to Treg homeostasis and instability in human peripheral blood.
We acknowledge the support from National Institutes of Health (awards P01 HL136275 and R35 HL145241) to K.L.
Lymphocyte Differentiation and Peripheral Maintenance (LYM)
Smriti Parashar, P. Roy, Mohammad Oliaeimotlagh et al.· Journal of Immunology· 0 citations
Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation and glutathione (GSH) depletion and represents a therapeutic vulnerability in hepatocellular carcinoma (HCC). While canonical ferroptosis regulation centers on cystine uptake and GPX4-mediated GSH utilization, the endogenous metabolic pathways governing ferroptosis sensitivity in liver tumors remain incompletely understood. Here, using a metabolic-scale CRISPR activation screen integrated with transcriptomic and metabolomic analyses, we identify L-2-hydroxyglutarate dehydrogenase (L2HGDH) as a potent antagonist of ferroptosis in HCC. We demonstrate that L2HGDH is frequently suppressed in liver tumors, leading to pathological accumulation of its substrate L-2-hydroxyglutarate (L2HG). Elevated L2HG sensitizes HCC cells to ferroptosis both in vitro and in vivo. Mechanistically, L2HG acts as a metabolic-epigenetic regulator that inhibits 2-oxoglutarate-dependent dioxygenases, induces histone hypermethylation, and remodels chromatin accessibility to activate an ATF3-dependent transcriptional program. This program induces the glutathione-degrading enzyme CHAC1, thereby accelerating GSH degradation to 5-oxoproline and disrupting redox homeostasis. Notably, L2HG-induced ferroptosis occurs independently of impaired cystine uptake, transsulfuration pathway activity, or increased GPX4-mediated GSH utilization, revealing a non-canonical ferroptosis mechanism driven by enhanced GSH catabolism. Consistent with these findings, genetic targeting of L2HGDH suppresses tumor growth, elevates L2HG levels, enhances GSH degradation, and promotes ferroptosis in HCC xenograft models. Collectively, our study identifies the L2HGDH-L2HG axis as a previously unrecognized metabolic checkpoint controlling ferroptosis sensitivity in liver cancer and uncovers glutathione degradation as a therapeutically exploitable vulnerability for ferroptosis-based treatment strategies in HCC.
Caixia Xi, Junfeng Pang, Mohammad Oliaeimotlagh et al.· Cell Death and Disease· 1 citation
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
