GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE345nnn/GSE345988/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE345988GEOGSEfalseMitophagy-dependent metabolic checkpoint controls seeding of HIV-1 latent reservoirAchieving a functional cure for HIV-1 remains a major challenge due to the persistence of highly stable viral latent reservoirs under long-term antiretroviral therapy (ART), particularly within resting memory CD4+ T cells. Current cure strategies have largely focused on reducing established reservoirs, with limited attention given to early interventions that could prevent reservoir seeding and contribute to post-treatment control. The cellular mechanisms that govern latent reservoir establishment are still not well understood. Here, we identified mitochondrial damage and mitophagy as defining features of effector-to-memory transitioning (EMT) CD4+ T cells, the primary targets for latent infection. Inhibiting mitophagy triggered ferroptosis, thereby impairing memory CD4+ T cell formation. Specifically, CCR5+ EMT CD4+ T cells, which are critical for latent reservoir seeding, displayed elevated mitochondrial damage and relied on mitophagy for survival. Pharmacological blockade of mitophagy selectively prevented the formation of CCR5+ EMT-derived memory CD4+ T cells, reduced latent HIV-1 infection, and significantly delayed viral rebound after ART interruption in an HIV-1-infected humanized mouse model. Together, these findings reveal a novel strategy to block latent reservoir seeding by inducing ferroptosis in CCR5+ EMT CD4+ T cells, offering a promising avenue for achieving sustained viral remission and advancing efforts toward a functional cure for AIDS.2026/10/01GSE345988GSM10020973GSM10020972GSM10020971GSM10020970GSM10020969GSM1002097416791345988Homo sapiens