# Treatment of Inflammatory Bowel Disease with Drugs Targeting PANoptosis: A Comprehensive Review

## TL;DR

This review explores how targeting PANoptosis, a combined form of inflammatory cell death, could lead to new treatments for inflammatory bowel disease.

## Contribution

The paper introduces PANoptosis as a novel therapeutic target and highlights challenges in translating preclinical findings to clinical success.

## Key findings

- Preclinical studies show that targeting PANoptotic regulators like RIPK1 and ZBP1 can restore intestinal barrier integrity.
- Clinical trials of pyroptosis inhibitors like Anakinra and RIPK1 inhibitors like GSK2982772 have shown disappointing results in IBD patients.
- Combination therapies or modulators of the PANoptosome may be more effective than single-pathway inhibition.

## Abstract

Background: Inflammatory Bowel Disease (IBD) involves a complex interplay between immune dysregulation and intestinal barrier failure. Traditional views focused on individual cell death pathways, but the emerging concept of PANoptosis—a coordinated inflammatory cell death involving apoptosis, necroptosis, and pyroptosis—offers a more holistic understanding of IBD pathogenesis. Objective: This review evaluates the role of PANoptosis in IBD, identifies key molecular triggers (such as the ZBP1-ADAR1 axis), and discusses the therapeutic potential of targeting this process. Methods: We analyzed recent literature and clinical trial data regarding programmed cell death (PCD) inhibitors and natural compounds in IBD models. Results: Preclinical data suggest that targeting PANoptotic regulators like RIPK1 and ZBP1 can restore barrier integrity. However, clinical translation remains challenging; for instance, while targeting pyroptosis via IL-1/IL-18 (Anakinra) showed promise in theory, clinical results in IBD have been disappointing. Furthermore, RIPK1 inhibitors such as GSK2982772 have failed to meet primary endpoints in Phase 2 trials. Conclusions: PANoptosis is a “hot” therapeutic target, but successful treatment likely requires combination therapies or “PANoptosome” specific modulators rather than single-pathway inhibition.