Dietary α-Ketoglutarate delays lung adenocarcinoma in females and modulates TBX5-associated transcriptional programs and the immune microenvironment
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Lung adenocarcinoma (LUAD) is the most common form of lung cancer and a leading cause of cancer-related mortality, underscoring the need for new chemopreventive strategies. α-Ketoglutarate (α-KG), a tricarboxylic acid cycle metabolite and dioxygenase cofactor, links cellular metabolism to chromatin regulation. Here, we show that dietary α-KG remodels LUAD in a sex-dependent manner. In female mice, α-KG reduced tumor area, decreased repressive histone marks (H3K27me3, H3K9me3), and upregulated TBX5 and myogenesis-associated genes. In male mice, α-KG-treated male mice exhibited increased tumor area, elevated H3K27me3, and immune remodeling characterized by CD8⁺ T cell expansion and transcriptomic signatures of T cell exhaustion. Analysis of human LUAD revealed that TBX5 expression is enriched in female tumors and associated with improved survival, suggesting it may serve as a marker of favorable outcome. Together, these findings support α-KG as an epigenetic modulator with potential chemopreventive activity in lung cancer and highlight the importance of incorporating sex as a biological variable in preclinical studies.
Summary
Oral α-Ketoglutarate (α-KG) has a known anti-aging effect and has been suggested to inhibit cancer development. However, the role of α-KG in lung cancer is not known. Here, we investigated the effect of oral α-KG on the development of lung adenocarcinoma in a Kras G12D -driven murine model. In females, α-KG reduced lung tumor growth, accompanied by TBX5 induction, activation of a myogenesis transcriptional program, and loss of repressive histone methylation. In males, α-KG increased tumor growth, coinciding with TBX5 repression, suppression of myogenesis programs, and accumulation of repressive histone methylation. α-Ketoglutarate also remodeled the tumor immune microenvironment in a sex-dependent manner, with divergent effects on T cell infiltration.
HIGHLIGHTS
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Oral α-Ketoglutarate reduces lung adenocarcinoma development in a genetically engineered murine model in a sex-dependent manner
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In females, α-Ketoglutarate reduces repressive histone marks and induces TBX5/myogenesis
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In males, α-Ketoglutarate increases repressive histone marks and suppresses TBX5/myogenesis
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α-Ketoglutarate remodels the tumor immune microenvironment with sex-specific effects
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TBX5 is enriched in female LUAD patients and predicts improved survival in human datasets
CONTEXT AND SIGNIFICANCE
Lung adenocarcinoma (LUAD) is the most common form of lung cancer and a leading cause of cancer mortality worldwide. Preventive strategies are limited, highlighting the need for safe approaches that can intercept tumor progression. Metabolic cofactors are increasingly recognized as modulators of the cancer epigenome. Among these, α-Ketoglutarate (α-KG), a central metabolite of the tricarboxylic acid cycle, functions as a cofactor for chromatin-modifying enzymes. Here, we demonstrate that dietary α-KG supplementation limits LUAD progression in female mice, reduces repressive histone methylation, and activates TBX5-associated transcriptional programs. These effects are sex dependent, underscoring the importance of biological context in shaping metabolic responses. In human LUAD, TBX5 is enriched in females and predicts improved survival, suggesting that it may serve as a marker of favorable outcome and help guide future studies of α-KG. Together, this work identifies α-KG as an epigenetically active metabolite with translational promise for lung cancer chemoprevention.
GRAPHICAL ABSTRACT
One-sentence summary
α-Ketoglutarate remodels lung adenocarcinoma through sex-dependent epigenetic, transcriptional, and immune reprogramming.
