Myeloma Novel Drug Targets and agents

Category: Myeloma Novel Drug Targets and agents

AKR1B1/NAT10 mediate IL4I1 ac4C modification to regulate tryptophan metabolism and promote multiple myeloma proliferation

(PA-324) AKR1B1/NAT10 Mediate IL4I1 ac4C Modification to Regulate Tryptophan Metabolism and Promote Multiple Myeloma Proliferation

Friday, September 19, 2025

Rongfang Wei, PhD

3025 Shennan Middle Road, Shenzhen, China
Department of Hematology, The Eighth Affiliated Hospital, Sun Yat-sen University

Introduction: Multiple myeloma (MM) is a malignant plasma cell tumor with a rising annual incidence rate and cannot be cured. Identifying novel molecular targets for the diagnosis and treatment of MM, as well as improving patient outcomes, is a crucial step in both basic and clinical research. Metabolic disorder is a significant factor in the poor prognosis of MM patients. Aldo-keto reductase family 1 member B1 (AKR1B1), which regulates glucose metabolism, participates in regulating the occurrence and development of various tumors, but its role in MM remains unclear.

Methods:   Analysis of AKR1B1 expression and prognosis in MM patients via gene expression profiling. Immunohistochemistry (IHC) and Western blot (WB) were employed to detect AKR1B1 expression. Co-immunoprecipitation (Co-IP)/MS and RNA sequencing (RNA-seq) were used to screen interacting proteins and key downstream targets of AKR1B1. The impact of AKR1B1 on cell proliferation was assessed through CCK-8, soft agar assays, and xenograft models. Acetylated RNA immunoprecipitation sequencing (acRIP-seq) and mRNA decay analysis were conducted to identify and validate critical downstream targets. Targeted metabolomics was applied to identify differential metabolites in MM cells. Nuclear-cytoplasmic fractionation assays were performed to examine protein nuclear translocation.

Results:   Elevated AKR1B1 expression was significantly associated with shorter overall survival (TT2: P = 0.0019; TT3: P = 0.0003). IHC staining revealed higher AKR1B1 levels in bone marrow tissues of MM patients (n = 20) compared to normal controls (n = 8). AKR1B1 overexpression promoted MM cell growth. KEGG analysis of RNA-seq data indicated that AKR1B1 induced dysregulation of the MAPK signaling pathway, metabolic pathways, and apoptosis. Mechanistic validation demonstrated that AKR1B1 activates p-38 expression, while AKR1B1 knockdown induced cleaved PARP and cleaved Caspase 3 expression to accelerate apoptosis. Co-IP/MS revealed an interaction between AKR1B1 and N-acetyltransferase 10 (NAT10). AKR1B1 interacts with NAT10 to promote interleukin-4-induced 1 (IL4I1) mRNA acetylation, enhancing its translation efficiency and driving MM progression. Targeted metabolomics demonstrated that IL4I1, regulated by AKR1B1, facilitates tryptophan metabolism in MM cells. Tryptophan metabolism was closely linked to activation of the aryl hydrocarbon receptor (AHR) signaling pathway. The reactome enrichment analysis of RNA-seq data highlighted AKR1B1’s role in modulating AHR signaling. Overexpression of AKR1B1 and IL4I1 promoted AHR nuclear translocation, while AKR1B1 knockdown inhibited this process, indicating that AKR1B1/IL4I1 activates the AHR pathway.

Conclusions:   AKR1B1 emerges as a novel regulator of ac4C modification and tryptophan metabolism, and targeted inhibition of AKR1B1 may offer a promising therapeutic strategy for MM.