Screening-based repurposing identifies potassium dehydroandrographolide succinate (KDAS) as a selective suppressor of TNF-α-induced caspase-8-dependent apoptosis in colonic epithelial cells
| dc.contributor.author | Valero-Cortijo, Alvaro | |
| dc.contributor.author | Shoenenberger-Arnaiz, Joan Antoni | |
| dc.contributor.author | Yuste Mateos, Víctor J. (Víctor José) | |
| dc.contributor.author | Ribas i Fortuny, Judit | |
| dc.date.accessioned | 2026-07-27T10:49:02Z | |
| dc.date.available | 2026-07-27T10:49:02Z | |
| dc.date.issued | 2026 | |
| dc.description.abstract | Under physiological conditions, tumor necrosis factor-α (TNF-α) favors cell survival through cytoprotective checkpoints, including a FIP200-dependent non-canonical autophagy pathway. Disruption of this checkpoint shifts TNF-α signaling toward apoptosis, a process relevant to epithelial injury in inflammatory bowel disease (IBD). Anti-TNF-α biologics are standard IBD therapy but primarily neutralize extracellular TNF-α without reducing epithelial susceptibility to death. Here, we conducted a two-step screen of 2421 clinically approved compounds in TNF-α-challenged FIP200-deficient cells to identify drugs that restore cytoprotection. Potassium dehydroandrographolide succinate (KDAS) emerged as a top candidate and conferred > 85% cytoprotection in FIP200-deficient HCT116 cells by inhibiting TNF-α-induced, caspase-8-dependent apoptosis without affecting necroptosis. Other andrographolides did not confer cytoprotection, highlighting KDAS specificity. KDAS also suppressed TRAIL-induced apoptosis and protected additional human cell lines and primary human colonic epithelial cells. Although KDAS enhanced early NF-κB and ERK signaling, pharmacological inhibition of these pathways did not abrogate cytoprotection, suggesting that they are dispensable for its protective effect. These findings identify KDAS as a candidate cytoprotective compound capable of preserving epithelial cell viability downstream of TNF-α receptor activation and indicate a pharmacological approach to limit epithelial apoptosis in TNF-α-mediated diseases such as IBD. | |
| dc.description.sponsorship | This work was funded by the “Ministerio de Ciencia, Innovación y Universidades”/Fondos FEDER (PID2020-114034RB-100) and the “Agency for Management of University and Research” (2022 FISDU 00101 to A.V-C). | |
| dc.identifier.doi | https://doi.org/10.1038/s41598-026-55892-0 | |
| dc.identifier.issn | 2045-2322 | |
| dc.identifier.uri | https://hdl.handle.net/10459.1/470997 | |
| dc.language.iso | en | |
| dc.publisher | Nature Portfolio | |
| dc.relation | info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-114034RB-I00/ES/REPOSICIONAMIENTO CONTRA EL CROHN: CRIBADO DE UNA LIBRERIA DE FARMACOS APROBADOS POR FDA QUE FRENEN LA MUERTE CELULAR POR TNF-A EN MODELOS GENETICOS DEFICIENTES EN AUTOFAGIA./ | |
| dc.relation.isformatof | Versió postprint del document publicat a: https://doi.org/10.1038/s41598-026-55892-0 | |
| dc.relation.ispartof | Scientific Reports, 2026 [Epub ahead of print] | |
| dc.rights | cc-by-nc-nd (c) The Authors, 2026 | |
| dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 International | * |
| dc.rights.accessRights | info:eu-repo/semantics/openAccess | |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
| dc.subject | Apoptosis | |
| dc.subject | Caspase-8 | |
| dc.subject | FIP200 | |
| dc.subject | Intestinal epithelial cells | |
| dc.subject | Potassium dehydroandrographolide succinate | |
| dc.subject | TNF-α | |
| dc.title | Screening-based repurposing identifies potassium dehydroandrographolide succinate (KDAS) as a selective suppressor of TNF-α-induced caspase-8-dependent apoptosis in colonic epithelial cells | |
| dc.type | info:eu-repo/semantics/article | |
| dc.type.version | info:eu-repo/semantics/acceptedVersion |