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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,5,27]]},"abstract":"<jats:p>Small-cell lung cancer (SCLC) is the most lethal type of lung cancer, characterized by rapid evolution from chemosensitivity to chemoresistance and limited treatment options. However, the mechanisms underlying this evolution remain poorly understood. Here, we show that Retinoid X receptor \u03b3 (RXR\u03b3) is uniquely overexpressed in chemo-resistant SCLC tumors, and that RXR\u03b3 serves as an essential factor driving chemoresistance in SCLC. RXR\u03b3 forms phase-separated droplets with LSD1 in the nucleus, which enhances RXR\u03b3-mediated gene transcription activity and reprograms gene expression, promoting tumor stemness and metastasis, and eventually driving SCLC chemoresistance. In turn, RXR\u03b3 antagonist disrupts RXR\u03b3\u2013LSD1 interaction, reducing their binding to the target gene locus, markedly suppressing the expression of the RXR\u03b3 target gene network. Finally, RXR\u03b3 antagonists strongly suppress tumor growth and metastasis and restore SCLC vulnerability to chemotherapy in multiple preclinical SCLC models, resulting in a substantial extension of survival in mouse models. Thus, these results establish RXR\u03b3 as a key player in SCLC by phase separation and as a potential therapeutic target for this deadly disease.<\/jats:p>","DOI":"10.1073\/pnas.2421199122","type":"journal-article","created":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T13:40:02Z","timestamp":1747748402000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":8,"title":["Phase separation of RXR\u03b3 drives tumor chemoresistance and represents a therapeutic target for small-cell lung cancer"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-5031-6593","authenticated-orcid":false,"given":"Hong","family":"Wang","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University","place":["Guangzhou, Guangdong, 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