Ferroptosis, a form of oxidative cell death, represents a therapeutic vulnerability for treating apoptosis-resistant cancers. Here, we identify leucine zipper transcription factor-like 1 (LZTFL1) as a key regulator of ferroptosis that rewires glutathione (GSH) metabolism. Mechanistically, LZTFL1 promotes oxidation of glucose-6-phosphate dehydrogenase (G6PD), thereby limiting NADPH production and impairing GSH regeneration. GSH depletion in turn enhances LZTFL1 translation via an AKT-mammalian target of rapamycin (mTOR)-eukaryotic initiation factor 4E (eIF4E) pathway, establishing a feedforward loop that amplifies ferroptosis. In vivo, the LZTFL1-formin homology 2 domain-containing 1 (FHOD1)-G6PD axis sensitizes multiple tumor models, including patient-derived xenografts, to ferroptosis, leading to enhanced lipid peroxidation, reduced GSH levels, suppressed tumor growth, and prolonged survival. LZTFL1 expression restores cisplatin sensitivity in resistant lung and ovarian cancer cells and predicts improved survival outcomes in patients with lung adenocarcinoma. Moreover, FDA-approved agents upregulate LZTFL1 and re-sensitize resistant tumors to cisplatin. These findings highlight LZTFL1 as a potential biomarker and a therapeutic target for enhancing ferroptosis-based cancer therapy.
Xiangfei Xue, Xiao Zhang, Qianjun Zhou et al.· Molecules and Cells· 0 citations
Trained immunity enhances innate host defense by endowing monocytes with memory-like properties, yet the underlying integrated metabolic and epigenetic mechanisms remain elusive. Here, we demonstrate that coimmunization with Bacille Calmette-Guérin (BCG) and bacterial lipoprotein (BLP) induces a durable form of trained immunity that provides robust, long-term protection against polymicrobial sepsis from early life into adulthood. Single-cell RNA sequencing revealed that this effect is mediated by an expansion of CCR5hi memory-like monocytes with enhanced antimicrobial capacity. Mechanistically, BCG + BLP vaccination activated the AKT–mTOR–HIF-1α axis, driving glycolytic reprogramming and lactate accumulation. Elevated lactate enhanced KAT2B-dependent histone H3K18 lactylation, an epigenetic mark directly facilitating the transcription of phagocytic and inflammatory genes. In addition, BCG + BLP stimulation of human cord blood mononuclear cells induced CCR5hi monocytes that recapitulated trained immunity features. These findings identify a lactate-KAT2B-H3K18la epigenetic axis that orchestrates the long-term reprogramming of CCR5hi monocytes, highlighting CCR5hi monocytes as a promising therapeutic target for modulating innate immunity against lethal sepsis.
Lingqi Xu, Wenyan Hao, Yingyi Yang et al.· Science Advances· 0 citations
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