Hydrogen Sulfide Rescues Microglia From HIV Tat‐Driven Ferroptosis: Implications for HIV ‐Associated Neuroinflammation

Aim HIV transactivator of transcription (Tat) protein induces oxidative stress, neuroinflammation, and glial dysfunction in NeuroHIV. Ferroptosis, an iron‐dependent form of regulated cell death driven by lipid peroxidation, has emerged as a contributor to HIV‐associated neurocognitive disorders. This study aimed to determine whether hydrogen sulfide (H 2 S) mitigates HIV Tat‐induced ferroptosis in microglial cells. Methods BV2 microglial cells were pretreated with sodium hydrosulfide (NaHS; 100 μM), an H 2 S donor, followed by exposure to recombinant HIV Tat (100 ng/mL, 48 h). Ferroptotic indices, including cytosolic Fe 2+ accumulation, lipid peroxidation, reactive oxygen species (ROS) generation, and cell membrane damage, were assessed using fluorescence‐based assays and lactate dehydrogenase (LDH) release. Expression of ferroptosis‐related and antioxidant proteins was analyzed by western blotting, and proinflammatory cytokine release was quantified by qPCR. Results NaHS pretreatment significantly attenuated HIV Tat‐induced Fe 2+ accumulation, ROS generation, lipid peroxidation, and LDH release. Mechanistically, NaHS suppressed pro‐ferroptotic mediators, acyl‐CoA synthetase long‐chain family member 4 (ACSL4) and 4‐hydroxynonenal (4‐HNE), while restoring solute carrier family 7‐member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression. NaHS also reduced HIV Tat‐induced IL1β, IL6, and TNFα secretion. Conclusion These findings demonstrate that H 2 S protects HIV Tat‐exposed microglia by suppressing ferroptosis and restoring cellular homeostasis. Collectively, these results identify H 2 S signaling as a promising mechanistic target for further investigation in NeuroHIV‐associated neuroinflammation.