上海交通大学医学院侯健研究团队宣布他们探明了Lipin1依赖的SREBPs转录失活增强多发性骨髓瘤对selinexor的敏感性性。2025年4月14日，国际知名学术期刊《中国药理学报》发表了这一成果。

在这项研究中，小组采用catTFRE蛋白质组学技术分析了SEL治疗后骨髓瘤细胞中活化转录因子(TFs)/辅助因子（TCs）核丰度的变化。课题组研究人员发现，SEL对输出素-1（XPO1）的药理学抑制导致NCI-H929细胞中Lipin1的显著核积累。核定位的Lipin1作为转录辅助因子抑制SREBPs的转录活性。通过亚细胞定位分析、分子对接、共免疫沉淀等实验，课题组人员证实Lipin1受xpo1依赖性核输出的影响。

该团队证明，SEL下调SREBPs调控的关键脂肪生成相关基因的表达，包括FASN、SCD、DHCR24和FDPS，导致MM细胞系和原代CD138⁺细胞中脂肪酸和胆固醇合成减少。通过shRNA介导的敲低实验，该课题组在体外和小鼠异种移植模型中阐明了Lipin1在介导SEL对SREBPs通路的抑制作用及其对SEL敏感性的贡献。总之，研究人员揭示了SEL下调细胞脂质生物合成从而抑制骨髓瘤细胞增殖的新机制。这项研究强调了Lipin1在SEL抗骨髓瘤作用中的关键作用，表明它有可能作为一种生物标志物，用于识别最有可能从基于SEL的治疗中获益的患者。

据悉，选择性核输出抑制剂selinexor（SEL）是治疗复发/难治性多发性骨髓瘤（RRMM）的一种有前景的治疗策略。但其作用机制以及影响治疗反应的因素尚未完全确定。

附：英文原文

Title: Lipin1-dependent transcriptional inactivation of SREBPs contributes to selinexor sensitivity in multiple myeloma

Author: Wang, Jun-ying, Chen, Meng-ping, Jiang, Jin-xing, Wan, Yi-ke, Li, Xin, Zhang, Yi-wei, Fang, Yi, Huang, Hong-hui, Qin, Zhao-yu, Hou, Jian

Issue&Volume: 2025-04-14

Abstract: Selective nuclear export inhibitor selinexor (SEL) represents a promising therapeutic strategy for relapsed/refractory multiple myeloma (RRMM). But its mechanisms of action as well as factors that influence therapeutic responses have not been fully characterized yet. In this study we employed catTFRE proteomics technique to profile changes in nuclear abundance of activated transcription factors (TFs)/co-factors (TCs) in myeloma cells following SEL treatment. We found that pharmacological inhibition of exportin-1 (XPO1) by SEL leads to a significant nuclear accumulation of Lipin1 in NCI-H929 cells. Nuclear-localized Lipin1 acted as a transcriptional cofactor that suppressed the transcriptional activity of SREBPs. By performing subcellular localization analysis, molecular docking, co-immunoprecipitation and other assays, we demonstrated that Lipin1 was subjected to XPO1-dependent nuclear export. We demonstrated that SEL downregulated the expression of key lipogenesis-related genes regulated by SREBPs including FASN, SCD, DHCR24 and FDPS, leading to reduced fatty acid and cholesterol synthesis in MM cell lines and primary CD138+ cells. Using shRNA-mediated knockdown assays, we elucidated the critical role of Lipin1 in mediating the inhibitory effects of SEL on the SREBPs pathway and its contribution to SEL sensitivity both in vitro and in murine xenograft models. In conclusion, we reveal a novel mechanism by which SEL downregulates cellular lipid biosynthesis, thereby inhibiting the proliferation of myeloma cells. This study highlights the critical role of Lipin1 in the anti-myeloma effects of SEL, suggesting its potential as a biomarker for identifying patients who are most likely to benefit from SEL-based therapies.

DOI: 10.1038/s41401-025-01553-3

Source: https://www.nature.com/articles/s41401-025-01553-3