2. Academic Validation
  3. Long non-coding RNA FEZF1-AS1 suppresses ferroptosis in multiple myeloma cells through KIAA1429-mediated m6A modification

Long non-coding RNA FEZF1-AS1 suppresses ferroptosis in multiple myeloma cells through KIAA1429-mediated m6A modification

  • Hum Cell. 2025 Oct 14;38(6):178. doi: 10.1007/s13577-025-01274-z.
Qing Su 1,  Weiliang Liu 2,  Peijin Wang 3,  Mingyi Wang 4
Affiliations

Affiliations

  • 1 Department of Bone Oncology, Yantai Shan Hospital, Yantai, 264001, China.
  • 2 Department of Orthopedics, Qingdao Fifth People's Hospital, Qingdao, 266000, China.
  • 3 Department of Rehabilitation, The Fifth People's Hospital of Shunde District, No. 39 Donghua Road, Longjiang Town, Shunde District, Foshan, 528300, Guangdong, China.
  • 4 Department of Rehabilitation, The Fifth People's Hospital of Shunde District, No. 39 Donghua Road, Longjiang Town, Shunde District, Foshan, 528300, Guangdong, China. wangmingyi_med@163.com.
PMID: 41085851 DOI: 10.1007/s13577-025-01274-z
Abstract

Multiple myeloma (MM) is a hematologic malignancy characterized by abnormal clonal plasma cells in the bone marrow. This study aims to investigate the mechanism by which the long non-coding RNA FEZF1 antisense RNA 1 (FEZF1-AS1) regulates Ferroptosis in MM cells through KIAA1429-mediated N6-methyladenosine (m6A) modification, and to identify novel therapeutic targets for MM therapy. The expression levels of FEZF1-AS1, Vir-like m6A methyltransferase associated protein (KIAA1429, also known as also known as VIRMA), and OTU Deubiquitinase, ubiquitin aldehyde-binding 1 (OTUB1) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. Cellular viability, Reactive Oxygen Species (ROS) accumulation, glutathione (GSH) levels, ferrous iron (Fe2+) concentration, malondialdehyde (MDA) content, and the protein levels of solute carrier family 7 member 11 (SLC7A11), Glutathione Peroxidase 4 (GPX4), and acyl-CoA synthetase long-chain family member 4 (ACSL4) were assessed. The interaction between FEZF1-AS1 and insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), as well as the interaction between IGF2BP3 and KIAA1429, was validated using RNA pull-down and RNA immunoprecipitation (RIP) assays. m6A and YTH N6-methyladenosine RNA-binding protein 1 (YTHDF1) on OTUB1 messenger RNA (mRNA) was analyzed. The stability of KIAA1429 mRNA and OTUB1 mRNA was also evaluated. In addition, the binding of OTUB1 to SLC7A11 and the ubiquitination status of SLC7A11 were determined by co-immunoprecipitation assays. The results showed that FEZF1-AS1, KIAA1429, and OTUB1 were highly expressed in MM cells. Knockdown of FEZF1-AS1 reduced cell viability and promoted Ferroptosis. Mechanistically, FEZF1-AS1 bound to IGF2BP3, which enhanced the stability and expression of KIAA1429 mRNA. KIAA1429 facilitated m6A modification on OTUB1 mRNA, thereby promoting OTUB1 expression through YTHDF1. OTUB1 in turn stabilized SLC7A11 expression by deubiquitination. Overexpression of either KIAA1429 or OTUB1 partially reversed the pro-ferroptotic effect induced by FEZF1-AS1 inhibition in MM cells.

Keywords

Ferroptosis; KIAA1429; LncRNA FEZF1-AS1; Multiple myeloma; OTUB1.

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