Integrative multi-omics and Mendelian randomization identify WWOX and THBS2 as potential therapeutic targets in mature T/NK-cell lymphoma

Qin et al. Journal of Translational Medicine (2025) 23:1306 https://doi.org/10.1186/s12967-025-07301-9 Journal of Translational Medicine Open Access RESEARCH Integrative multi-omics and Mendelian randomization identify WWOX and THBS2 as potential therapeutic targets in mature T/NKcell lymphoma Yinjie Qin1, Jiayue Wei1, Yingzhi He1, Yeqin Zheng1, Yuchang Lin1, Ziwei Liu1 and Yuxian Huang1* Abstract Background 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. Methods 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. Results 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. Conclusions 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. Keywords Mature T/NK-cell lymphoma, Mendelian randomization, Quantitative trait loci, Therapeutic target *Correspondence: Yuxian Huang 1 Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, China © The Author(s) 2025. 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To view a copy of this licence, visit http://creati vecommons.org/licenses/by-nc-nd/4.0/. Qin et al. Journal of Translational Medicine (2025) 23:1306 Introduction Mature T/NK-cell lymphomas are a highly heterogeneous group of aggressive non-Hodgkin lymphomas originating from mature T cells or natural killer (NK) cells. Their pathological subtypes mainly include extranodal NK/Tcell lymphoma (ENKTCL), peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), systemic anaplastic large cell lymphoma (sALCL), angioimmunoblastic T-cell lymphoma (AITL), and primary cutaneous T-cell lymphomas, among others [1]. These diseases are often characterized by complex diagnosis, strong invasiveness, and poor prognosis. The efficacy of traditional chemotherapy regimens for patients with mature T/NK-cell lymphomas is typically unsatisfactory. Although optimizing drug regimens can improve the effective remission rate in initially treated patients, long-term survival data remain pessimistic for patients with relapsed/refractory (R/R) and advanced disease, with an average overall survival of approximately 6 months [1–3]. In recent years, treatment strategies for mature T/NK-cell lymphomas have progressively shifted from monotherapy with conventional chemotherapy to multimodal approaches, including targeted therapy, immunotherapy, and combination regimens, demonstrating promising potential for sustained disease control [4–6]. Although molecular targeted therapy and immunotherapy have achieved certain breakthroughs, a unified standardized treatment protocol has not yet been established, and their efficacy has not fully surpassed the survival bottleneck of traditional chemotherapy. Overall, individualized and precision treatment based on molecular typing and genetic variations represents the future trend. There is an urgent need for in-depth research into the biological heterogeneity and pathogenesis of mature T/NK-cell lymphomas to explore more effective treatment strategies. Mendelian Randomization (MR) is an effective statistical method in genetic epidemiology that infers causality using genetic variants, primarily single nucleotide polymorphisms (SNPs), as instrumental variables (IVs) [7]. This approach adheres to Mendel’s laws of inheritance, where genetic variants are randomly allocated during gamete formation, a process independent of postnatal environmental factors, thereby effectively controlling for confounding effects of the environment. Genome-wide association studies (GWAS) are a research method based on high-throughput genotyping technologies, aimed at identifying genetic variants significantly associated with specific phenotypes (such as diseases, traits, biomarkers, etc.) through genome-wide screening of large-scale population cohorts [8]. With the rapid growth of GWAS data and the widespread availability of related genetic data, MR analysis, utilizing the genetic variants associated with risk factors revealed by these data, has been widely applied in various fields including disease risk factor Page 2 of 18 identification, drug efficacy evaluation, and drug target development [9, 10]. For instance, by employing genetic variants related to systolic blood pressure within multiple antihypertensive drug target gene loci as genetic proxies for the drugs, MR analysis has demonstrated a negative association between the effects of these antihypertensive drugs and t (...truncated)