Martín Alcaraz, Aparamita Pandey, Mia Santiago, Camelia Dumitras, Leilani Pradis, Estefany Gomez, Adriana Soto, Pasquale Saggese, Abigail S Krall, Bin Liu, Heather R Christofk, Steven M Dubinett, Xue Li, Claudio Scafoglio
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 (αKG), a tricarboxylic acid cycle metabolite and dioxygenase cofactor, links cellular metabolism to chromatin regulation. Here, we demonstrate that dietary calcium αKG (Ca-αKG) is associated with remodeling of LUAD in a sex-dependent manner. In female mice, Ca-αKG is associated with reduced tumor area, decreased repressive histone marks (H3K27me3 and H3K9me3), and upregulated TBX5 and myogenesis-associated genes. In male mice, Ca-αKG is associated with increased tumor area and elevated H3K27me3. 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 Ca-αKG 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.