A moonlighting function of tumoral interleukin-1β precursor promotes metastasis via RACK1-mediated actin remodeling

Quanzhu Chen, Pan Wu, Jing Cai, Xingxing Lu, Zhaojian Gong, Pan Chen, Zhaoyang Zeng, Guiyuan Li, Wei Xiong, Mei Yi () and Bo Xiang ()
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Quanzhu Chen: Central South University, NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine
Pan Wu: Central South University, NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine
Jing Cai: Central South University, Department of Pathology, The Second Xiangya Hospital
Xingxing Lu: Central South University, NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine
Zhaojian Gong: Central South University, Department of Oral and Maxillofacial Surgery, The Second Xiangya Hospital
Pan Chen: Central South University, NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine
Zhaoyang Zeng: Central South University, NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine
Guiyuan Li: Central South University, NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine
Wei Xiong: Central South University, NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine
Mei Yi: FuRong Laboratory
Bo Xiang: Central South University, NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Interleukin-1β (IL-1β) is a key inflammatory mediator in cancer. Its precursor, Pro-IL-1β, is conventionally considered inactive. Here we demonstrate that head and neck squamous cell carcinoma (HNSCC) cells exhibit significantly elevated Pro-IL-1β expression, driven by super-enhancer-mediated transcription of the IL1B gene. We show that intracellular Pro-IL-1β promotes tumor invasion and metastasis independent of IL-1β processing. Mechanistically, Pro-IL-1β binds RACK1 and inhibits its UBE2T-mediated ubiquitination, thereby stabilizing RACK1 and activating RhoA signaling to induce actin cytoskeleton remodeling and pseudopodia formation. Genetic inhibition of RACK1 abolishes Pro-IL-1β-induced metastasis. Clinically, RACK1 protein levels correlate with Pro-IL-1β expression in HNSCC specimens. Furthermore, we identify the natural compound Q3MG as a direct binder of Pro-IL-1β; it promotes lysosomal degradation of Pro-IL-1β and suppresses metastatic progression both in vitro and in vivo. Our study reveals a non-canonical, moonlighting function of Pro-IL-1β in tumor progression and highlights Q3MG as a promising therapeutic agent against metastatic cancer.

Date: 2025
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DOI: 10.1038/s41467-025-65220-1

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