2. Academic Validation
  3. Identification of Pinostilbene as a natural STING agonist that triggers FTH1 degradation via K48-ubiquitination to induce ferroptosis in non-small cell lung cancer

Identification of Pinostilbene as a natural STING agonist that triggers FTH1 degradation via K48-ubiquitination to induce ferroptosis in non-small cell lung cancer

  • Redox Biol. 2026 Apr:91:104099. doi: 10.1016/j.redox.2026.104099.
Shuangshuang Song 1,  Siqi Hua 1,  Guo Chen 2,  Xianrui Yin 3,  Zhengguo Chen 3,  Chong Li 4,  Danyang Zhou 5,  Bo Zhu 6
Affiliations

Affiliations

  • 1 School of Biopharmacy, China Pharmaceutical University, Nanjing, 211198, China.
  • 2 School of Biopharmacy, China Pharmaceutical University, Nanjing, 211198, China; Shandong Province Key Laboratory of Polymorphic Drugs, Shandong Yikang Pharmaceutical Co., Ltd., Tengzhou, 277500, China.
  • 3 Department of Nuclear Medicine, Mianyang Central Hospital, Mianyang, 621000, China.
  • 4 Department of Oncology, Dazu Hospital of Chongqing Medical University, Chongqing, 402360, China. Electronic address: [email protected].
  • 5 Department of Respiratory, Nanjing First Hospital, China Pharmaceutical University, Nanjing, 210012, China. Electronic address: [email protected].
  • 6 School of Biopharmacy, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: [email protected].
PMID: 41723905 DOI: 10.1016/j.redox.2026.104099
Abstract

Non-small cell lung Cancer (NSCLC) treatment faces significant challenges due to drug resistance and toxicity. Emerging evidence suggests that Ferroptosis, an iron-dependent form of regulated cell death, is a promising therapeutic strategy. We identify Pinostilbene, a natural stilbenoid, as a potent and novel STING agonist. Our findings reveal that Pinostilbene effectively activates the STING/TBK1/IRF3 pathway, leading to the transcriptional upregulation of downstream cytokines. Importantly, we demonstrate that Pinostilbene significantly enhances the sensitivity of lung Cancer cells to RSL3-induced Ferroptosis. Mechanistically, Pinostilbene promotes the degradation of the iron-storage protein Ferritin Heavy Chain 1 (FTH1), a key negative regulator of Ferroptosis. We uncover a novel mechanism in which Pinostilbene induces FTH1 degradation through the ubiquitin-proteasome system via K48-linked polyubiquitination, a process independent of NCOA4-mediated ferritinophagy. This FTH1 degradation increases the labile iron pool, a critical prerequisite for Ferroptosis. In vivo, Pinostilbene exhibits robust antitumor efficacy alone and achieves synergistic tumor growth inhibition when combined with RSL3 in a NSCLC mouse model without systemic toxicity. Its therapeutic effect is linked to STING activation and FTH1 downregulation, which coincides with an increase in the Ferroptosis biomarker 4-HNE. Furthermore, Pinostilbene enhances antitumor immunity by upregulating inflammatory cytokines and promoting the infiltration and activation of tumor-killing CD8+ T cells, alongside drving anti-tumor M1 polarization of macrophages. Our study highlights the potential of Pinostilbene as a promising therapeutic agent for NSCLC, offering a multifaceted mechanism of action through Ferroptosis sensitization and immunostimulation.

Keywords

Antitumor immunity; FTH1; Ferroptosis; Pinostilbene; STING agonist; Ubiquitination.

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