Leukocyte immunoglobulin-like receptor B1 (LILRB1) protects human multiple myeloma cells from ferroptosis by maintaining cholesterol homeostasis

Miao Xian, Qiang Wang, Liuling Xiao, Ling Zhong, Wei Xiong, Lingqun Ye, Pan Su, Chuanchao Zhang, Yabo Li, Robert Z. Orlowski, Fenghuang Zhan, Siddhartha Ganguly, Youli Zu, Jianfei Qian and Qing Yi ()
Additional contact information
Miao Xian: Houston Methodist Research Institute
Qiang Wang: Houston Methodist Research Institute
Liuling Xiao: Houston Methodist Research Institute
Ling Zhong: Houston Methodist Research Institute
Wei Xiong: Houston Methodist Research Institute
Lingqun Ye: Houston Methodist Research Institute
Pan Su: Houston Methodist Research Institute
Chuanchao Zhang: Houston Methodist Research Institute
Yabo Li: Houston Methodist Research Institute
Robert Z. Orlowski: The University of Texas MD Anderson Cancer Center
Fenghuang Zhan: University of Arkansas for Medical Sciences
Siddhartha Ganguly: Houston Methodist Research Institute
Youli Zu: Institute for Academic Medicine, Houston Methodist Research Institute
Jianfei Qian: Houston Methodist Research Institute
Qing Yi: Houston Methodist Research Institute

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Multiple myeloma (MM) is a hematologic malignancy characterized by uncontrolled proliferation of plasma cells in the bone marrow. MM patients with aggressive progression have poor survival, emphasizing the urgent need for identifying new therapeutic targets. Here, we show that the leukocyte immunoglobulin-like receptor B1 (LILRB1), a transmembrane receptor conducting negative immune response, is a top-ranked gene associated with poor prognosis in MM patients. LILRB1 deficiency inhibits MM progression in vivo by enhancing the ferroptosis of MM cells. Mechanistic studies reveal that LILRB1 forms a complex with the low-density lipoprotein receptor (LDLR) and LDLR adapter protein 1 (LDLRAP1) to facilitate LDL/cholesterol uptake. Loss of LILRB1 impairs cholesterol uptake but activates the de novo cholesterol synthesis pathway to maintain cellular cholesterol homeostasis, leading to the decrease of anti-ferroptotic metabolite squalene. Our study uncovers the function of LILRB1 in regulating cholesterol metabolism and protecting MM cells from ferroptosis, implicating LILRB1 as a promising therapeutic target for MM patients.

Date: 2024
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DOI: 10.1038/s41467-024-50073-x

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