Objectives <p>To investigate the role of lncRNA PVT1 in modulating CD4⁺ T cell subsets and its contribution to systemic lupus erythematosus (SLE) pathogenesis in human patients and MRL/lpr mice.</p> Methods <p>Measured PVT1 and miR-30e-5p expression in SLE patients (<i>n</i> = 65) and healthy controls (HCs) using qRT-PCR. Analyzed Th1/Th2/Th17/Treg cell frequencies by flow cytometry and cytokine levels (IL-2, IL-4, IL-6, IL-17, TGF-β) via ELISA. Constructed lentiviral vectors to silence (SLE + si-<i>Pvt1</i>) or overexpress <i>Pvt1</i> (SLE + lenti-<i>Pvt1</i>) in MRL/lpr mice (<i>n</i> = 40).</p> Results <p>PVT1 was upregulated (<i>p</i> = 0.0488) and miR-30e-5p downregulated (<i>p</i> = 0.0095) in SLE patients. Th2 (<i>p</i> = 0.0165) and Th17 (<i>p</i> = 0.0017) cells exhibited a significant increase, while Th1 and Treg cells decreased. <i>Pvt1</i> silencing reversed SLE phenotypes, increasing Th1 and Treg cells, reducing Th2 and Th17 cells, restoring IL-2 and TGF-β levels and reducing levels of IL-6 and IL-17. Overexpression of <i>Pvt1</i> exacerbated disease severity. <i>Pvt1</i> acted as a ceRNA to sponge miR-30e-5p, modulating T-bet/GATA3/RORγt/Foxp3 expression.</p> Conclusions <p>PVT1 dysregulation disrupts CD4⁺ T cell homeostasis in SLE. Targeting the PVT1/miR-30e-5p axis may restore immune balance and represent a novel therapeutic strategy.<Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry align="left" nameend="c2" namest="c1"> <p><i>Key Points</i></p> <p>• <i>Our data confirm the imbalance of CD4+ T cell subsets in SLE patients and demonstrate specific upregulation of lncRNA PVT1 expression in female SLE patients.</i></p> <p>• <i>Targeting lncRNA PVT1 affects Th1/Th2 and Th17/Treg homeostasis in MRL/lpr mice.</i></p> <p>• <i>Offers fresh insight into the dysregulation of lymphocyte subsets in SLE.</i></p> </entry> </row> </tbody> </tgroup> </Table></p>