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 (H2S) mitigates HIV Tat-induced ferroptosis in microglial cells.

METHODS

BV2 microglial cells were pretreated with sodium hydrosulfide (NaHS; 100 μM), an H2S donor, followed by exposure to recombinant HIV Tat (100 ng/mL, 48 h). Ferroptotic indices, including cytosolic Fe2+ 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 Fe2+ 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 H2S protects HIV Tat-exposed microglia by suppressing ferroptosis and restoring cellular homeostasis. Collectively, these results identify H2S signaling as a promising mechanistic target for further investigation in NeuroHIV-associated neuroinflammation.