2. Academic Validation
  3. DDX1 crotonylation mediates ACOX1 alternative splicing through HNRNPK to increase peroxisomal oxidative damage

DDX1 crotonylation mediates ACOX1 alternative splicing through HNRNPK to increase peroxisomal oxidative damage

  • Free Radic Biol Med. 2026 Jan:242:549-567. doi: 10.1016/j.freeradbiomed.2025.11.004.
Jiansong Liu 1,  Shuo Wang 2,  Changyu Tao 3,  Haoyun Liu 4,  Yutong Mao 2,  Xinhui Zhao 2,  Kaiqi Cheng 4,  Guanqun Mu 2,  Meng Wang 2,  Weibin Wang 4,  Ence Yang 5,  Jiadong Wang 6,  Yang Yang 7
Affiliations

Affiliations

  • 1 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China; Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
  • 2 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China.
  • 3 Department of Human Anatomy, Histology & Embryology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 4 Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
  • 5 Department of Medical Bioinformatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China. Electronic address: [email protected].
  • 6 Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China. Electronic address: [email protected].
  • 7 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China. Electronic address: [email protected].
PMID: 41197750 DOI: 10.1016/j.freeradbiomed.2025.11.004
Abstract

Peroxisomes are essential organelles that maintain cellular redox homeostasis. Although alternatively spliced variants of certain peroxisome-related genes have been identified, the regulatory mechanisms governing alternative splicing (AS) and its functional impact on peroxisomal redox homeostasis remain poorly understood. Here, we demonstrate that glucose starvation (GS) induces crotonylation of DEAD-box helicase 1 (DDX1), which is regulated by the crotonyltransferase general control non-repressed protein 5 (GCN5) and the decrotonylase histone deacetylase 1 (HDAC1). DDX1 crotonylation at the lysine 490 residue enhances its interaction with heterogeneous nuclear ribonucleoprotein K (HNRNPK), which mediates mutually exclusive AS of acyl-CoA oxidase 1 (ACOX1). The AS of ACOX1, driven by DDX1 crotonylation and HNRNPK, promotes the generation of peroxisomal ROS, thereby enhancing oxidative damage and ultimately suppressing colorectal Cancer (CRC) cell proliferation. Our findings uncover a novel mechanism by which DDX1 crotonylation regulates the AS of peroxisome-related genes and mediates peroxisomal redox homeostasis. This discovery bridges a critical gap in our understanding of how posttranslational modifications (PTMs) of DEAD/DEXD box RNA helicases modulate gene AS and identifies a potential therapeutic target for colorectal Cancer.

Keywords

ACOX1; Alternative splicing; Crotonylation; DDX1; HNRNPK.

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