Screening-based repurposing identifies potassium dehydroandrographolide succinate (KDAS) as a selective suppressor of TNF-α-induced caspase-8-dependent apoptosis in colonic epithelial cells.

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.