Longitudinal changes in ferroptosis-related and inflammatory biomarkers during treatment of pulmonary tuberculosis: a...

Ferroptosis-related mechanisms may contribute to macrophage injury in tuberculosis, but circulating markers cannot by themselves establish ferroptotic cell death. We characterized longitudinal changes in a ferroptosis-related and inflammatory biomarker panel during standard treatment for pulmonary tuberculosis.

In this prospective longitudinal case-control study at a chest clinic in Wasit Province, Iraq, 30 adults with newly diagnosed pulmonary tuberculosis were assessed before treatment, after 2 months and at completion (6 months); 30 healthy controls were assessed once. Whole-leukocyte GPX4 and ACSL4 mRNA and serum 4-hydroxynonenal (4-HNE), soluble ST2 (sST2), interleukin-33 (IL-33), ferritin, iron and lactate dehydrogenase (LDH) were measured, with Holm adjustment for multiple comparisons. At baseline, patients had lower GPX4 expression and serum iron but higher ACSL4 expression, 4-HNE, sST2, IL-33, ferritin and LDH than controls (all p < 0.0001, also after covariate adjustment). During treatment GPX4 and serum iron rose while the other six markers fell. At 6 months, ACSL4 and LDH remained different from controls after correction; sST2 and serum iron differed in unadjusted comparisons only; no difference was detected for GPX4, 4-HNE, IL-33 or ferritin. Apparent (derivation-sample) areas under the curve were 0.997 (95% CI 0.982-1.000) for GPX4, 0.995 (0.977-1.000) for ACSL4 and 1.000 (1.000-1.000) for LDH.

Active pulmonary tuberculosis was associated with a treatment-responsive circulating profile consistent with altered ferroptosis-related biology. The measurements do not establish ferroptotic cell death, its cellular source, tuberculosis specificity or monitoring utility. Validation in larger cohorts with clinically relevant disease controls is required.