{
  "abstract": "Novel anticancer agents are needed to overcome therapeutic resistance, and autophagy represents a promising target. The chlorinated alkylphenones Dictyostelium differentiation-inducing factors 1 and 3 (DIF-1 and DIF-3) and their derivatives exert anti-proliferative and anti-metastatic effects; however, their molecular mechanisms remain incompletely understood. Using the GFP-LC3-RFP-LC3ΔG autophagic flux reporter, we identified Bu-DIF-3 and CP-DIF-3 as autophagy-promoting derivatives and characterized their actions principally in HeLa cells, with selected autophagy and AMP-activated protein kinase (AMPK) measurements in HAP1 cells. Both suppressed mTORC1 signaling, activated AMPK, and reduced mitochondrial membrane potential (MMP). Bu-DIF-3 additionally induced reactive oxygen species and redox stress response genes, including SLC7A11 and CHAC1. SLC7A11 induction may reflect a compensatory antioxidant response. Unlike CP-DIF-3, Bu-DIF-3 increased the FerroOrange-detectable labile Fe2+ signal, and deferoxamine partially restored the reduced MTT signal, supporting possible iron involvement in reduced metabolic activity. Thus, modification of the DIF-3 methoxy group modulates autophagy-promoting activity and associated stress responses. Bu-DIF-3 was associated with oxidative stress and altered labile Fe2+ homeostasis; whether a ferroptosis-related mechanism contributes remains unresolved. These findings provide a cellular basis for further evaluation of Bu-DIF-3 and related DIF derivatives.",
  "abstract_shown": true,
  "affiliations": [
    "Laboratory of Food and Life Science, Institute of Human Sciences, Waseda University, Saitama 359-1192, Japan",
    "Department of Food and Health Sciences, International College of Arts and Sciences, Fukuoka Women’s University, Fukuoka 813-8529, Japan",
    "Division of Natural Medicines, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan",
    "Faculty of Health and Sports Science, Juntendo University, Chiba 270-1695, Japan"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yue Cai"
    },
    {
      "affs": [
        0
      ],
      "name": "Ryu Yamada"
    },
    {
      "affs": [
        0
      ],
      "name": "Yuki Marugame"
    },
    {
      "affs": [
        0
      ],
      "name": "Satoshi Yano"
    },
    {
      "affs": [
        1
      ],
      "name": "Fumihiko Okumura"
    },
    {
      "affs": [
        2
      ],
      "name": "Haruhisa Kikuchi",
      "orcid": "0000-0001-6938-0185"
    },
    {
      "affs": [
        3
      ],
      "name": "Yuzuru Kubohara",
      "orcid": "0000-0001-9231-9833"
    },
    {
      "affs": [
        0
      ],
      "name": "Taichi Hara",
      "orcid": "0000-0002-4722-6336"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/96v1gjp6f3d23.bib",
  "cited_by": 0,
  "doi": "10.3390/ijms27209380",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13705388/?tool=EBI",
  "id": "96v1gjp6f3d23",
  "issns": [
    "1422-0067"
  ],
  "landing_url": "https://www.mdpi.com/1422-0067/27/20/9380",
  "language": "eng",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2713|Autophagy in Disease and Therapy"
    ]
  ],
  "openalex": "W7223297372",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13705388/pdf/?tool=EBI",
  "pmcid": "PMC13705388",
  "pmid": null,
  "published": "2026-10-01",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/96v1gjp6f3d23.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:57Z",
      "native_id": "10.3390/ijms27209380",
      "source": "crossref",
      "url": "https://www.mdpi.com/1422-0067/27/20/9380"
    },
    {
      "first_seen": "2026-10-30T12:21:34Z",
      "native_id": "PMC:PMC13705388",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13705388"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2713|Autophagy in Disease and Therapy",
      "subfield": "epidemiology-public-health"
    }
  ],
  "title": "Derivatives of Dictyostelium Differentiation-Inducing Factor-3 Promote Autophagic Flux, Mitochondrial Dysfunction and Iron-Associated Oxidative Stress",
  "title_text": "Derivatives of Dictyostelium Differentiation-Inducing Factor-3 Promote Autophagic Flux, Mitochondrial Dysfunction and Iron-Associated Oxidative Stress",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:21:34Z",
  "url": "https://research.draconitic.com/paper/96v1gjp6f3d23",
  "venue": "International Journal of Molecular Sciences",
  "versions": []
}