{
  "abstract": "Ulcerative colitis (UC) is an intestinal inflammatory disorder primarily driven by M1 macrophage activation and oxidative stress. p62/Sequestosome-1, a multifunctional autophagy adaptor protein, plays a critical role in regulating autophagy and inflammation. α-Methylene-γ-butyrolactone (αMγB), a conserved structural motif found in anti-inflammatory sesquiterpene lactones from traditional medicinal herbs, was shown to suppress M1 macrophage activation and inflammation. This study aimed to investigate the role of p62 in UC pathogenesis and evaluate the therapeutic potential of αMγB. We found that genetic deletion of p62 aggravated disease severity in both acute pneumonia and UC mouse models. Treatment with αMγB alleviated UC symptoms by reprogramming macrophage polarization, reshaping the mucosal immune microenvironment, and suppressing inflammatory crosstalk between macrophages and epithelial cells. Mechanistically, αMγB covalently modified p62 at C291, preventing its ubiquitination and stabilizing it, which enhanced Keap1 binding and drove its autolysosomal degradation. This process released Nrf2, facilitated its nuclear translocation, and activated the expression of downstream antioxidant and anti-inflammatory genes. Importantly, αMγB established a positive feedback loop between Nrf2 and p62 that sustained p62 upregulation and further promoted Keap1 autolysosomal degradation. These protective effects were abolished in p62 (C291S) mutant mice or upon Nrf2 inhibition. Collectively, our findings demonstrated that αMγB ameliorated UC by specifically targeting p62 at C291, promoting its stabilization, and enhancing Keap1 degradation, thereby modulating macrophage polarization. These findings highlighted the therapeutic potential of αMγB and suggested that augmenting p62 function might represent a promising strategy for UC treatment.",
  "abstract_shown": true,
  "affiliations": [
    "State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine & School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, Guizhou, 561113, China.",
    "Department of Anus and Intestinal Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550 025, China.",
    "State Key Laboratory of Mechanism and Quality of Chinese Medicine, University of Macau, Taipa, Macau, China.",
    "General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China; School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: duqianming@njmu.edu.cn.",
    "State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine & School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, Guizhou, 561113, China. Electronic address: wdpan@gmc.edu.cn."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "name": "Ke-Gang Linghu"
    },
    {
      "name": "Dasong Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Tian Zhang"
    },
    {
      "name": "Fei Jiang"
    },
    {
      "affs": [
        1
      ],
      "name": "Long Wu"
    },
    {
      "name": "Di Pan"
    },
    {
      "name": "Yan Chen"
    },
    {
      "name": "Ling Tao"
    },
    {
      "affs": [
        2
      ],
      "name": "Ligen Lin"
    },
    {
      "affs": [
        2
      ],
      "name": "Hua Yu"
    },
    {
      "affs": [
        3
      ],
      "name": "Qianming Du"
    },
    {
      "affs": [
        4
      ],
      "name": "Weidong Pan"
    },
    {
      "name": "Xiangchun Shen"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5tk7b4tzv0nca.bib",
  "cited_by": 0,
  "doi": "10.1016/j.redox.2026.104424",
  "fulltext_url": "https://europepmc.org/articles/PMC13675664",
  "id": "5tk7b4tzv0nca",
  "issns": [
    "2213-2317"
  ],
  "landing_url": "https://europepmc.org/article/MED/42849356",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1311|Inflammatory Bowel Disease"
    ]
  ],
  "openalex": "W7218656010",
  "pdf_url": "https://europepmc.org/articles/PMC13675664?pdf=render",
  "pmcid": "PMC13675664",
  "pmid": "42849356",
  "published": "2026-10-03",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/5tk7b4tzv0nca.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:10Z",
      "native_id": "MED:42849356",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42849356"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1311|Inflammatory Bowel Disease",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "Disruption of p62 ubiquitination by α-methylene-γ-butyrolactone enhances Keap1 lysosomal degradation for ulcerative colitis therapy.",
  "title_text": "Disruption of p62 ubiquitination by α-methylene-γ-butyrolactone enhances Keap1 lysosomal degradation for ulcerative colitis therapy.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:18:10Z",
  "url": "https://research.draconitic.com/paper/5tk7b4tzv0nca",
  "venue": "Redox biology",
  "versions": []
}