KEAP1 promoter hypermethylation in human cancers: a meta-analysis of case-control studies

Kelch-like ECH-associated protein 1 (KEAP1) regulates the NRF2 signaling pathway and plays a critical role in oxidative stress response and tumor suppression. Promoter hypermethylation of KEAP1 may contribute to carcinogenesis; however, its association with cancer remains unclear.

A systematic review and meta-analysis were conducted following PRISMA 2020 guidelines. PubMed, Scopus, Web of Science, and the Cochrane Library were searched up to July 29, 2025. Eligible case-control studies were included. Pooled odds ratios (ORs) were calculated using a random-effects model. Heterogeneity, subgroup effects, publication bias, and robustness were assessed using standard meta-analytic approaches.

Seven studies comprising 407 cancer cases and 158 controls were included. KEAP1 promoter hypermethylation was significantly associated with cancer presence (OR = 13.66; 95% CI 4.89-38.14; p < 0.001), with moderate heterogeneity (I² = 42.1%). Subgroup analyses indicated that heterogeneity was largely explained by cancer type and methylation detection method, with strong associations observed in lung and other cancers but not in colorectal cancer. Studies using qMSP showed more consistent and stronger effects than MSP-based studies. Publication bias was suggested by Egger's test (p = 0.006), and trim-and-fill analysis indicated potential overestimation of the pooled effect. Sensitivity analyses using the Hartung-Knapp-Sidik-Jonkman and GLMM approaches supported the robustness of the findings.

KEAP1 promoter hypermethylation is significantly associated with cancer in case-control studies. Although findings were consistent across multiple analyses, potential bias and limited study numbers warrant cautious interpretation.