This study examined how Bcl-xL (encoded by *BCL2L1*) drives gastric tumorigenesis using APC-deficient mouse models, gastric organoids, and xenografts — with findings validated in human gastric cancer tissue and databases.
Bcl-xL deletion reduced tumor growth and proliferation via two mechanisms: enhancing Wnt/β-catenin signaling (suppressing HNF4α and PPARγ) and dampening PPARγ-driven metabolic pathways. In human data, high *BCL2L1* expression correlated with elevated Wnt target genes and poor prognosis; high *PPARG* expression correlated with better outcomes. Epidemiological data suggested pioglitazone (a PPARγ agonist) lowered gastric cancer incidence in diabetic patients.
Findings are based largely on mouse models (APC-deletion driven) and xenografts, which may not fully reflect the heterogeneity of human gastric cancer. The epidemiological pioglitazone data is associative and cannot establish causality. Validation in prospective human cohorts is lacking.
BCL-xL and PPARγ may be viable therapeutic targets in gastric cancer; clinicians should be aware that pioglitazone use in diabetic patients was associated with reduced gastric cancer incidence in this epidemiological analysis, though confirmatory trials are needed before practice changes.
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