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<p>Biomaterials have underpinned tissue engineering, drug delivery, and disease treatment for over 80 years, yet their clinical translation is hampered by unclear molecular mechanisms. Fullerene derivatives like 6M1@C60 exhibit antioxidant/anti-inflammatory potential for atherosclerosis but lack defined therapeutic targets. We integrated multi-databases (GeneCards, TTD, OMIM, CTD) and used ChatGPT-4 with chain-of-thought reasoning to predict 6M1@C60 targets; 11 candidates were identified, and NRF2 was experimentally validated. In ApoE<sup>⁻/⁻</sup> mice, high-dose 6M1@C60 reduced aortic plaque area, lowered ferroptosis markers (4-HNE, MDA, Fe²⁺), and improved oxidative stress (reduced TG, TC, LDL, ox-LDL). In vitro, it suppressed Erastin-induced RAW264.7 macrophage ferroptosis (decreased ROS/LPO, increased GSH/GSSG)—effects reversed by the NRF2 inhibitor ML385 and rescued by GPX4 overexpression. Linking LLM-driven prediction to mechanistic validation, we show 6M1@C60 attenuates atherosclerosis via NRF2/HO-1/GPX4-mediated ferroptosis regulation. These findings provide a theoretical basis for fullerene clinical application and highlight LLMs’ utility in biomaterial target discovery.</p> Graphical Abstract <p></p>

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LLMs uncover 6M1@C60’s therapeutic targets: inhibiting atherosclerotic progression via NRF2/HO-1/GPX4 axis-mediated ferroptosis suppression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月2日

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  • Wenhao Liu,
  • Guofeng Zhou,
  • Xin Gao,
  • Bo Li,
  • Yingjie Zhao

摘要

Biomaterials have underpinned tissue engineering, drug delivery, and disease treatment for over 80 years, yet their clinical translation is hampered by unclear molecular mechanisms. Fullerene derivatives like 6M1@C60 exhibit antioxidant/anti-inflammatory potential for atherosclerosis but lack defined therapeutic targets. We integrated multi-databases (GeneCards, TTD, OMIM, CTD) and used ChatGPT-4 with chain-of-thought reasoning to predict 6M1@C60 targets; 11 candidates were identified, and NRF2 was experimentally validated. In ApoE⁻/⁻ mice, high-dose 6M1@C60 reduced aortic plaque area, lowered ferroptosis markers (4-HNE, MDA, Fe²⁺), and improved oxidative stress (reduced TG, TC, LDL, ox-LDL). In vitro, it suppressed Erastin-induced RAW264.7 macrophage ferroptosis (decreased ROS/LPO, increased GSH/GSSG)—effects reversed by the NRF2 inhibitor ML385 and rescued by GPX4 overexpression. Linking LLM-driven prediction to mechanistic validation, we show 6M1@C60 attenuates atherosclerosis via NRF2/HO-1/GPX4-mediated ferroptosis regulation. These findings provide a theoretical basis for fullerene clinical application and highlight LLMs’ utility in biomaterial target discovery.

Graphical Abstract