2. Academic Validation
  3. A LNK-CBL-HNRPA2B1-GPX4 signaling axis mediates dopaminergic neuron vulnerability to ferroptosis in Parkinson's disease

A LNK-CBL-HNRPA2B1-GPX4 signaling axis mediates dopaminergic neuron vulnerability to ferroptosis in Parkinson's disease

  • Redox Biol. 2026 Mar:90:104039. doi: 10.1016/j.redox.2026.104039.
Ziqi Liu 1,  Ruoxun Wang 1,  Min Shen 1,  Xinrui Lan 1,  Weixing Yan 2,  Sainan Wang 1,  Mingfeng Jiang 1,  Rongqing Li 1,  Jie Zhao 1,  Qicheng Wang 1,  Xinyi Xv 1,  Jingwen Zhou 1,  Xin Pan 3,  Wei Li 4,  Weijuan Gong 5,  Li Qian 6
Affiliations

Affiliations

  • 1 Key Laboratory of the Jiangsu Higher Education Institutions for Nucleic Acid & Cell Fate Regulation (Yangzhou University), Faculty of Medicine, Yangzhou University, Yangzhou, Jiangsu, 225001, China.
  • 2 Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
  • 3 Department of Cardiology, Institute of Cardiovascular Disease, Yangzhou Key Lab of Innovation Frontiers in Cardiovascular Disease, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, 225001, China. Electronic address: [email protected].
  • 4 Kunshan Hospital of Chinese Medicine, Affiliated Hospital of Yangzhou University, Kunshan, Jiangsu, 215300, China. Electronic address: [email protected].
  • 5 Key Laboratory of the Jiangsu Higher Education Institutions for Nucleic Acid & Cell Fate Regulation (Yangzhou University), Faculty of Medicine, Yangzhou University, Yangzhou, Jiangsu, 225001, China. Electronic address: [email protected].
  • 6 Key Laboratory of the Jiangsu Higher Education Institutions for Nucleic Acid & Cell Fate Regulation (Yangzhou University), Faculty of Medicine, Yangzhou University, Yangzhou, Jiangsu, 225001, China. Electronic address: [email protected].
PMID: 41616574 DOI: 10.1016/j.redox.2026.104039
Abstract

The upstream mechanisms governing neuronal susceptibility to Ferroptosis in Parkinson's disease (PD) remain incompletely defined. This study investigates the molecular pathways mediating dopaminergic neuron vulnerability to Ferroptosis in PD. The Lymphocyte adaptor protein (LNK) is identified as an upstream regulator, with its expression being significantly increased in peripheral blood of PD patients and positively associating with motor impairment severity. Similar upregulation occurs in murine PD models, coinciding with enhanced neuronal susceptibility. LNK interacts with the E3 ubiquitin Ligase casitas B-lineage lymphoma proto-oncogene (CBL), promoting nuclear translocation and K27-linked polyubiquitination-driven degradation of the RNA-binding protein heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1). As an N6-methyladenosine (m6A) reader, HNRNPA2B1 stabilizes GPX4 transcripts, and its depletion reduces GPX4 levels, impairing glutathione-dependent lipid peroxidation defense. A pharmacological screen identifies lifitegrast an FDA-approved ophthalmic LFA-1 antagonist, as a putative small molecule modulator capable of interacting with the LNK SH2 domain and attenuating LNK-associated signaling in cellular assays. In PD models, lifitegrast administration or genetic ablation of LNK was observed to mitigate dopaminergic neurodegeneration. These findings define the LNK-CBL-HNRNPA2B1-GPX4 axis in ferroptotic regulation and support LNK as a potential therapeutic target in PD.

Keywords

Dopaminergic neurodegeneration; Ferroptosis; LNK; Lifitegrast; Parkinson's disease.

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