{
  "abstract": "Background Ulcerative colitis (UC) is characterized by low remission rates and frequent relapse, largely attributable to disruption of the intestinal epithelial barrier. Although ferroptosis has been implicated in UC pathogenesis, the lack of understanding regarding its upstream regulatory mechanisms hinders the development of targeted therapies. The ALOX15-PEBP1 complex, which functions as a ferroptosis ‘molecular switch’ under type 2 inflammatory conditions, has not been investigated in UC. This study aimed to explore the role of this complex in intestinal epithelial injury and to elucidate the therapeutic mechanism of Salvianolic acid A (Sal A).Methods A machine learning model (Bagging, ROC-AUC = 0.904) was used to screen a natural compound library, identifying Sal A as a potential ALOX15 inhibitor. Allosteric MD simulations (100 ns) and deep learning were used to study its disruption of the ALOX15-PEBP1 complex. Cellular assays (CCK-8, C11-BODIPY, Western blot) were performed on LPS-stimulated IEC-6 cells to evaluate anti-ferroptotic effects. Direct binding was confirmed by CETSA and DARTS, while complex disruption was validated by Co-IP and immunofluorescence. ALOX15 knockdown abolished Sal A’s effects, confirming target specificity. In vivo, colonic tissues from DSS-colitis mice were analyzed for ferroptosis and barrier markers; microbiota was assessed via 16S rRNA sequencing.Results Computational simulations demonstrated stable binding of Sal A to ALOX15. In vitro, Sal A (10–30 µM) dose-dependently restored cell viability, suppressed lipid peroxidation, and upregulated GPX4 expression. Mechanistically, Sal A directly bound to ALOX15 and specifically disrupted ALOX15-PEBP1 complex assembly; these protective effects were lost following ALOX15 knockdown. In the DSS-induced colitis model, Sal A (10 mg/kg, 20 mg/kg) significantly ameliorated clinical symptoms, reduced histological damage, restored Occludin and ZO-1 expression, and downregulated ALOX15, PEBP1, and ACSL4 in colonic tissue. Microbiota analysis revealed that Sal A enriched beneficial bacteria, particularly within the Lachnospiraceae family.Conclusions This study provides the first evidence that Salvianolic acid A alleviates ulcerative colitis by targeting ALOX15-PEBP1 complex assembly, thereby inhibiting intestinal epithelial ferroptosis ( IDDF2026-ABS-0078 Figure 1. Graphical Abstract). These findings highlight a novel mechanistic pathway and support the therapeutic potential of Sal A in UC. (Acknowledgements: This study was funded by National Natural Science Foundation of China (82370564))Abstract IDDF2026-ABS-0078 Figure 1",
  "authors": [
    {
      "affiliations": [
        "Guangdong Medical University, China"
      ],
      "name": "Lianxiang Luo"
    },
    {
      "affiliations": [
        "Guangdong Medical University, China"
      ],
      "name": "Jingli Ao"
    }
  ],
  "title": "IDDF2026-ABS-0078 Machine learning-driven discovery of salvianolic acid a targeting the ALOX15-PEBP1 complex to inhibit intestinal epithelial ferroptosis in ulcerative colitis",
  "uid": "46a521e2-b595-5ff0-89a8-4f0d0bb9344b"
}