Leukocyte Immunoglobulin-Like Receptor B1 (LILRB1) Protects Human Multiple Myeloma Cells From Ferroptosis by Maintaining Cholesterol Homeostasis

Authors

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
Qing Yi

Publication Date

7-9-2024

Journal

Nature Communications

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.

Keywords

Humans, Multiple Myeloma, Leukocyte Immunoglobulin-like Receptor B1, Ferroptosis, Homeostasis, Cholesterol, Receptors, LDL, Animals, Cell Line, Tumor, Mice, Antigens, CD, Myeloma, Cell death, Target identification

Comments

Supplementary Materials

Data Availability Statement

PMID: 38982045