GPX4 regulates cellular necrosis and host resistance in Mycobacterium tuberculosis infection

Abstract

Cellular necrosis during Mycobacterium tuberculosis (Mtb) infection promotes both immunopathology and bacterial dissemination. Glutathione peroxidase-4 (Gpx4) is an enzyme that plays a critical role in preventing iron-dependent lipid peroxidation–mediated cell death (ferroptosis), a process previously implicated in the necrotic pathology seen in Mtb-infected mice. Here, we document altered GPX4 expression, glutathione levels, and lipid peroxidation in patients with active tuberculosis and assess the role of this pathway in mice genetically deficient in or overexpressing Gpx4. We found that Gpx4-deficient mice infected with Mtb display substantially increased lung necrosis and bacterial burdens, while transgenic mice overexpressing the enzyme show decreased bacterial loads and necrosis. Moreover, Gpx4-deficient macrophages exhibited enhanced necrosis upon Mtb infection in vitro, an outcome suppressed by the lipid peroxidation inhibitor, ferrostatin-1. These findings provide support for the role of ferroptosis in Mtb-induced necrosis and implicate the Gpx4/GSH axis as a target for host-directed therapy of tuberculosis.

Pan-Cancer Analysis of the Role of the Ferroptosis-Related Biomarker GPX4: A Potential Target for Prognosis and Immunotherapy

“…There is evidence that GPX4 expression levels correlate with immune cell in ltration. Study showed that GPX4 was involved in some microbial infections, such as Mycobacterium tuberculosis (22). Recent study also showed that mice lacking GPX4 triggers focal granuloma-like neutrophilic enteritis when treating with a ω-6 polyunsaturated fatty acid (PUFA)-enriched Western diet (23).…”

Natural Flavonoids and Ferroptosis: Potential Therapeutic Opportunities for Human Diseases

“…Increasing evidence indicates that ferroptosis is involved in the occurrence and development of multiple human diseases. − Predictably, flavonoids that regulate ferroptosis-related promoting or monitoring molecules may influence the susceptibility of cells to ferroptosis and thus serve as potential therapeutic agents for clinical translation. In fact, flavonoids are a group of phenolic natural products that consist of a core 2-phenylchromone skeleton .…”

Mycobacterium tuberculosis-macrophage interaction: Molecular updates

“…Gpx4 is a crucial intracellular lipid peroxidation-detoxifying enzyme (Yant et al, 2003), and its inactivation not only participates in ferroptosis but also remains the main mechanism supporting this process (Krantz et al, 2005;Dixon et al, 2012;Yang et al, 2014). GPX4 and glutathione levels are reduced in active TB individuals, whereas those of free iron, mitochondrial superoxide, and lipid peroxidation are increased (Amaral et al, 2019;Amaral et al, 2022), suggesting a role of ferroptosis in Mtb infection. Besides, perturbed Fe2 + homeostasis is a TB risk factor and may serve as a TB diagnostic marker (Reddy et al, 2018;Dai et al, 2019;Meunier and Neyrolles, 2019).…”