Lactate Dehydrogenase B delactylation promotes gastric cancer metastasis via enhancing glutathione-mediated resistance to ferroptosis

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Abstract
Purpose To elucidate the role of protein lactylation in gastric adenocarcinoma progression, focusing on lactate dehydrogenase B (LDHB) delactylation at K58 and its effects on metastasis, glutathione (GSH) metabolism, and ferroptosis resistance. Methods Quantitative proteomics profiled lactylation in gastric adenocarcinoma versus adjacent normal tissues. Bioinformatics and Kaplan–Meier analyses assessed differentially lactylated genes and survival correlations. LDHB lactylation sites were validated via immunoprecipitation and Western blotting in lactate-stimulated cells. Functional assays evaluated LDHB-K58R (delactylation mimic) effects on proliferation, invasion, GSH levels, cystine uptake, STAT1/SLC7A11/GPX4 expression, and RSL3-induced ferroptosis in vitro. EMT markers were examined by immunofluorescence and Western blotting. In vivo lung metastasis was assessed in nude mice injected with modified AGS cells, treated with RSL3 or DMSO. Results Proteomics identified 121 upregulated and 53 downregulated lactylation sites in tumors, with LDHB as a key differentially lactylated protein. High LDHB expression correlated with poor progression-free and disease-specific survival. LDHB was primarily lactylated at K58; K58R delactylation enhanced proliferation, colony formation, invasion, cystine uptake, and SLC7A11-dependent GSH synthesis by suppressing STAT1 and downregulating GPX4, without affecting EMT or lactate release. K58R conferred robust resistance to RSL3-induced ferroptosis, reducing lipid ROS and preserving malignant phenotypes in vitro. In vivo, K58R promoted lung metastasis and suppressed RSL3-induced ferroptosis and lipid peroxidation (4-HNE). Conclusion LDHB-K58 delactylation drives gastric cancer metastasis via SLC7A11-mediated GSH synthesis and ferroptosis resistance, suggesting therapeutic targeting of this axis for overcoming therapy resistance. Graphical Abstract
Funding Information
  • the Natural Science Foundation of Sichuan Province, China (2023YSF0083)

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