整合多组学与孟德尔随机化鉴定 WWOX 和 THBS2 为成熟 T/NK 细胞淋巴瘤的潜在治疗靶点

Mature T/NK-cell lymphoma is a highly heterogeneous, aggressive non-Hodgkin lymphoma. Due to the lack of specific therapeutic targets, treatment outcomes for patients with relapsed/refractory (R/R) disease are limited, and survival rates are low. Therefore, there is an urgent need to explore specific therapeutic targets and treatment strategies based on molecular mechanisms.

Multi-omics data including genome-wide association study (GWAS), cis-expression quantitative trait loci (cis-eQTL), and cis-protein quantitative trait loci (cis-pQTL) were integrated through Mendelian Randomization (MR) and Bayesian colocalization analyses to identify and validate potential therapeutic targets. Summary-data-based MR (SMR) analysis strengthened causal inference, while cis-methylation quantitative trait loci (cis-mQTL) data integration elucidated genetic regulatory mechanisms. Transcriptome analysis assessed target biological functions, and phenome-wide MR evaluated the risk-benefit profile of target interventions. Drug prediction and molecular docking assessed therapeutic potential of these targets.

WWOX was identified as a protective factor and THBS2 as a risk factor, both with strong colocalization support. SMR analysis revealed close associations between WWOX expression, DNA methylation, and disease risk. Transcriptome analysis indicated that WWOX and THBS2 participate in tumor proliferation, invasion, and immune regulation. Phenome-wide MR analysis suggested that tissue-specific targeting is crucial for THBS2 inhibition. Drug prediction preliminarily validated the therapeutic potential of epigenetic regulatory drugs.

This study identifies WWOX and THBS2 as potential therapeutic targets for mature T/NK-cell lymphoma. Treatment strategies based on epigenetic reprogramming and immune microenvironment regulation targeting WWOX and THBS2 provide new directions for precision therapy of this refractory lymphoma.