The metabolite α-KG induces GSDMC-dependent pyroptosis through death receptor 6-activated caspase-8

TLDR

Pyroptosis is a regulated cell death pathway mediated by gasdermin proteins, but the role of GSDMC remains unclear. α‑Ketoglutarate, through its cell‑permeable derivative DM‑αKG, raises ROS that oxidizes death receptor DR6, triggering its endocytosis and recruitment of pro‑caspase‑8 and GSDMC to a receptosome; in acidic environments MDH1 converts α‑KG to L‑2HG, further amplifying ROS and enabling pyroptosis in otherwise resistant cells. α‑Ketoglutarate induces caspase‑8–mediated cleavage of GSDMC, causing pyroptosis that suppresses tumor growth and metastasis in mouse models, highlighting a metabolite‑driven pathway with therapeutic promise.

Abstract

Abstract Pyroptosis is a form of regulated cell death mediated by gasdermin family members, among which the function of GSDMC has not been clearly described. Herein, we demonstrate that the metabolite α-ketoglutarate (α-KG) induces pyroptosis through caspase-8-mediated cleavage of GSDMC. Treatment with DM-αKG, a cell-permeable derivative of α-KG, elevates ROS levels, which leads to oxidation of the plasma membrane-localized death receptor DR6. Oxidation of DR6 triggers its endocytosis, and then recruits both pro-caspase-8 and GSDMC to a DR6 receptosome through protein-protein interactions. The DR6 receptosome herein provides a platform for the cleavage of GSDMC by active caspase-8, thereby leading to pyroptosis. Moreover, this α-KG-induced pyroptosis could inhibit tumor growth and metastasis in mouse models. Interestingly, the efficiency of α-KG in inducing pyroptosis relies on an acidic environment in which α-KG is reduced by MDH1 and converted to L-2HG that further boosts ROS levels. Treatment with lactic acid, the end product of glycolysis, builds an improved acidic environment to facilitate more production of L-2HG, which makes the originally pyroptosis-resistant cancer cells more susceptible to α-KG-induced pyroptosis. This study not only illustrates a pyroptotic pathway linked with metabolites but also identifies an unreported principal axis extending from ROS-initiated DR6 endocytosis to caspase-8-mediated cleavage of GSDMC for potential clinical application in tumor therapy.