Regulator of G protein signaling 1 (RGS1) is known to be highly expressed in various tumors, but its specific effects and regulatory mechanism in ovarian cancer (OC) progression are not well understood. To delve into the tumor biology, a predictive risk model for OC was developed, incorporating RGS1, PRKG2, CD24, and ABCB1, with RGS1 exhibiting the strongest correlation. The model’s reliability and validity were confirmed through Kaplan-Meier analysis, receiver operating characteristic (ROC) curve, and principal component analysis (PCA). The risk score was validated as an independent indicator of overall survival, and a nomogram model was created to predict overall survival. Moreover, RGS1 expression was found to be up-regulated and associated with a poor prognosis in OC. Functional studies revealed that deleting RGS1 inhibited OC cell proliferation both in vitro and in vivo, while overexpression of RGS1 enhanced cell proliferation. Additionally, blocking the NF-kB pathway was shown to impede RGS1-induced proliferation, and overexpression of p65 partially reversed the effects of RGS1 deletion, promoting the tumorigenic properties of OC cells. These findings suggest that RGS1 could be a valuable biomarker for predicting prognosis and a potential novel therapeutic target for OC treatment.

Premature ovarian insufficiency (POI) is a major cause of infertility and endocrine dysfunction, in which chronic inflammation plays a critical role. The homeostasis of tissue‐resident macrophages and monocyte‐differentiated macrophages from peripheral blood serves as a key mechanism of inflammation across organs, yet their phenotypic plasticity in ovarian pathologies, including POI, remains poorly understood. Here, we identify that SIRT5 deficiency decreases macrophage count by attenuating monocyte‐macrophage differentiation. SIRT5 deficiency markedly attenuated follicular depletion and granulosa cell apoptosis, coinciding with reduced M1 macrophage infiltration and cytokine expression in the POI model. Mechanistically, we uncovered RAC2 as a novel succinylation substrate of SIRT5. SIRT5 deficiency elevated RAC2 succinylation, promoting its proteasomal degradation and thereby impairing CSF1R‐driven macrophage differentiation and M1 polarization. Pharmacological inhibition of SIRT5 recapitulated these protective effects, preserving follicular integrity and suppressing macrophage‐mediated inflammation. Our findings identify the SIRT5–RAC2 axis as a key regulator of ovarian immune homeostasis and establish SIRT5 as a proof‐of‐concept therapeutic target for POI.

Background: Tertiary lymphoid structures (TLSs) are spatial immune niches in solid tumors, but their relationship to mature regulatory dendritic-cell (mregDC) states in ovarian cancer remains incompletely resolved. Methods: We integrated public gynecological-tumor single-cell RNA sequencing, representative CD11C/HLA-DRA/LAMP3/CCR7 multiplex immunofluorescence, public Xenium and multi-sample spatial transcriptomics, TCGA-OV immune deconvolution and exploratory prognostic modeling, scTenifoldKnk and CellOracle perturbation analyses, and supplementary computational drug prioritization. Results: A $LAMP{3}^{+}CCR{7}^{+}$ dendritic-cell state showed mature migratory, antigen-presentation, checkpoint, and NF-$\kappa$B/TNF-associated programs. Spatial analyses linked TLS-score-defined regions to mregDC, antigen-presentation/MHC-II proxy, and interferon-associated signals, with distance-gradient analyses supporting TLS-proximal enrichment. Immune deconvolution associated the TLS/mregDC axis with an immune-infiltrated TCGA-OV contexture, whereas adjusted analyses emphasized dependence on broader immune-program richness. Perturbation analyses nominated candidate regulatory axes for experimental testing, and the supplementary drug-prioritization layer was retained only as target-class hypothesis support. Conclusions: These data support a hypothesis-generating model of a TLS-associated $LAMP{3}^{+}CCR{7}^{+}$ mregDC antigen-presentation program in ovarian cancer, while requiring raw-channel tissue validation, functional perturbation, and independent clinical testing.

Background The RGS1 protein and its regulators are key players in the development of different malignancies. The RGS1 gene was considered as a promising biomarker for ovarian cancer prognosis, and it was hypothesized that it would encourage proliferation via the NF-κB signaling pathway.Methods The data was gathered using the Cancer Genome Atlas (TCGA) database, the Human Protein Atlas (HPA) dataset, and the gene expression omnibus (GEO) database. The role of RGS1 in the development of OC was examined utilizing the CCK-8, EDU, Transwell, real-time PCR, and Western blotting assays. In nude mice, the impact of RGS1 on OC formation was confirmed.Results RGS1 was revealed to be a major determinant of OC prognosis. Functionally, although knockdown of RGS1 had the opposite effects, ectopic expression of RGS1 increased growth capacity in vitro and triggered tumor development in vivo. Additionally, RGS1 suppression caused OC cells to stop in the G1/S phase, which is in line with changes in cell-cycle components. In terms of mechanism, RGS1 knockdown inhibited the NF-κB signaling pathway.Conclusions RGS1 can be a target for cancer treatment since it performed an oncogenic function in the development of OC, in part via controlling the NF-κB signaling pathway.