PINK1 and Parkin are central regulators of mitophagy, a quality-control process essential for mitochondrial homeostasis and implicated in aging. However, their specific roles in ovarian physiology remain unclear. Here, we show that Pink1 deletion in mice leads to decreased ovarian weight, diminished ovarian reserve, and reduced oocyte quality, accompanied by increased granulosa cell apoptosis, accelerated ovarian ageing, and impaired fertility. Pink1 deficiency also compromises ovulation efficiency, increases oocyte cytoplasmic fragmentation, and disrupts meiotic spindle assembly, resulting in markedly reduced developmental competence of early embryos. Mechanistically, bulk and single-cell RNA sequencing reveal that loss of PINK1 impairs mitophagy and promotes transcriptional signatures of ovarian aging. In contrast, Parkin deletion exerts minimal effects on mitophagy, mitochondrial function, or ovarian physiology. Together, these findings identify PINK1, but not Parkin, as a critical regulator of ovarian aging through modulation of mitophagy.

Colorectal cancer (CRC) is one of the most common malignant tumors with the highest incidence and mortality rates worldwide. Immune checkpoint blockade (ICB) therapy has revolutionized the landscape of cancer treatment; however, most patients with CRC gain limited benefits from it. The immunosuppressive microenvironment of CRC is an important cause of tumor progression, metastasis, and immunotherapy resistance. This study aimed to reveal the key role of chemokine receptor 4 (CXCR4) in the immunosuppressive microenvironment and glutamine metabolism reprogramming using integrated single-cell transcriptomics and metabolomics analyses. The in vivo and in vitro experiments verified that CXCR4 mediated metabolic reprogramming in CRC cells by regulating the PI3K-Akt-SMAD4 pathway. Further co-culture experiments revealed that CXCR4 promoted the polarization of tumor-associated macrophages (TAMs) to M2 type through glutamine metabolic reprogramming and induced the exhaustion of CD8+ T cells, thereby intensifying immune escape. The knockdown of CXCR4 significantly increased the infiltration of CD8+ T cells and M1 TAMs, reduced the infiltration of M2 TAMs, effectively reshaped the immunosuppressive microenvironment of CRC-bearing mice, and significantly enhanced the immunotherapeutic effect against programmed cell death protein 1 (PD-1). This study discovered a novel mechanism by which CXCR4 drove CRC immune escape through the dual-axis regulation of the “glutamine metabolism-immune microenvironment.” Targeting CXCR4 not only inhibits tumor metabolic adaptability but also reverses TAMs polarization and T cell exhaustion, thereby effectively sensitizing PD-1 inhibitors. This study provides an important theoretical basis and a highly promising new combined treatment strategy for overcoming ICB resistance in patients with CRC.

Exosomes are key mediators of communication between tumor cells and the tumor microenvironment(TME); however, the mechanisms underlying exosome-mediated crosstalk between tumor cells and macrophages remain largely unclear. This study investigated the effect of exosomal RAB10 on macrophage polarization and tumor growth. Mechanistically, RAB10 delivered by breast cancer cells binds to the interferon receptor IFNAR1 and inhibits JAK1/STAT1 pathway phosphorylation, thereby impeding M1 polarization and promoting M2 polarization. RAB10 expression was significantly upregulated in drug-resistant breast cancer cells and was correlated with poor patient prognosis. In vitro assays confirmed that RAB10 enhances cancer cell proliferation. In vivo knockdown of RAB10 suppressed tumor growth and reduced the expression of markers related to proliferation (Ki67, PCNA), invasion (MMP2), and epithelial–mesenchymal transition (Snail, Vimentin). Single-cell RNA sequencing revealed a marked decrease in the proportion of macrophages in the TME following RAB10 knockdown. This phenotypic shift increases the secretion of immunosuppressive factors such as PDL1, leading to reduced activity of CD8⁺ T cells. Animal studies further confirmed that combined targeting of RAB10 and PD-L1 produces a synergistic inhibitory effect on tumor growth. This study demonstrated that breast cancer cells can transfer RAB10 to macrophages via exosomes. RAB10 interacts with IFNAR1 to suppress the JAK1/STAT1 signaling pathway, thereby inhibiting M1 polarization and promoting M2 polarization of macrophages. Inhibition of RAB10, especially in combination with PD-L1 blockade, offers a promising strategy to enhance anti-tumor immunity and overcome therapeutic resistance in breast cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype with limited therapeutic options and poor prognosis, creating an urgent demand for novel strategies. Sonodynamic therapy (SDT) is a promising non-invasive approach, yet its clinical translation is restricted by low efficacy of traditional sonosensitizers and single-modal limitations. In this study, we constructed a zinc‑copper‑iron-based layered double hydroxide (ZnCuFe@LDHs) nanoplatform integrating SDT with synergistic ferroptosis and cuproptosis for targeted TNBC treatment. In vitro experiments with 4 T1 cells demonstrated efficient cellular internalization and lysosomal escape of ZnCuFe@LDHs. Under ultrasound stimulation, the nanoplatform generated abundant reactive oxygen species (ROS) and released Cu2+/Fe3+ in response to the acidic tumor microenvironment (TME) and elevated intracellular glutathione (GSH). These events synergistically triggered ferroptosis by inactivating glutathione peroxidase 4 (GPX4) and accumulating lipid peroxide, while inducing cuproptosis through Cu2+ overload, mitochondrial dysfunction, tricarboxylic acid cycle disruption and lipoylated dihydrolipoamide acetyltransferase (DLAT) oligomerization. Additionally, ZnCuFe@LDHs triggered immunogenic cell death (ICD) characterized by calreticulin (CRT) exposure and high-mobility group box 1 (HMGB1) release, promoting dendritic cell maturation and antitumor immunity. In vivo studies using 4 T1 subcutaneous xenograft models confirmed significant tumor growth suppression by ZnCuFe@LDH and ultrasound, with no obvious systemic toxicity. Serum biochemical analysis and histological examination of major organs validated favorable biocompatibility. Collectively, ZnCuFe@LDHs achieves potent targeted antitumor efficacy via the integration of SDT, ferroptosis, cuproptosis, andimmunogenic cell death(ICD). This quadruple-modal synergistic strategy offers a safe and translational therapeutic option for TNBC.

This study aimed to investigate the multifaceted biological functions of RAB10 in the development and progression of breast cancer, with a specific focus on its role and molecular mechanisms in remodelling the tumour metabolic and immune microenvironments. Experimental results demonstrated that RAB10 promotes the expression of PPARγ and its downstream target gene DGAT1 via activation of the PI3K/AKT signalling pathway. This axis drives lipid metabolic reprogramming and inhibits ferroptosis, thereby enhancing breast cancer cells survival under stress. The functional state of RAB10 modulates the tumour microenvironment via tumour-derived exosomes. Upon uptake by macrophages, these exosomes transmit signals that promote M2 polarization and inhibit ferroptosis. Crucially, knocking down RAB10 inhibits PPARγ via the PI3K/AKT pathway, thereby blocking M2 polarization of tumour-associated macrophages and enhancing CD8+ T cell infiltration, thus reversing the immunosuppressive microenvironment. This study investigates the potential role of the RAB10/PI3K/AKT/PPARγ axis in remodelling the breast cancer microenvironment from the perspective of metabolic-immune crosstalk. These findings not only enhance the understanding of the interplay between metabolism and immune responses in the tumour microenvironment but also provide a potential theoretical foundation and novel research directions for combination treatment strategies targeting this pathway.

Background The peri-implantation period (days 6-14) is a metabolic checkpoint for embryonic viability, yet melatonin's role in this phase remains unclear despite its known benefits for early embryogenesis. Results In our in vitro embryo culture model, melatonin was undetectable in embryos during this window in both human and mice, yet MT1/MT2 receptors were expressed. Human metabolomic profiling characterized the dynamic changes of differential metabolites, including 5-methylcytosine, succinic acid, and PC (18:1/18:1), during the peri-implantation period, indicating that development at this stage is highly dependent on cell membrane construction, energy metabolism, and key signaling molecules. Further investigation into the role of melatonin revealed that its treatment reduces tryptophan and L-kynurenine levels while increasing nicotinic acid and enhancing NAD(+) synthesis. In mice, intraperitoneal melatonin increased NAD(+) levels in embryos and decidual tissue and delayed age-related NAD(+) decline in maternal serum. Conclusions Exogenous melatonin acts through its receptors to modulate tryptophan metabolism and NAD(+) synthesis, demonstrating its potential as a key hormonal regulator of embryonic development and reproductive capacity.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor prognosis. Treatment options of TNBC are limited, which is prone to recurrence and metastasis, posing a serious threat to patients' health. Recent studies revealed the important role of ferroptosis in TNBC. Vanillin is a phenolic aldehyde extracted from natural vanilla pods with multiple pharmacological activities, including anti-tumor properties. The present study aimed to explore the potential of vanillin in treating TNBC from the perspective of inducing ferroptosis. BT549 and MDA-MB-231 cells were incubated with 8 and 16 μM Vanillin for 24 h. Significantly decreased colony number, enhanced ROS, MDA, and GSSG levels, and reduced GSH levels and SOD activities in BT549 and MDA-MB-231 cells were triggered by 8 and 16 μM Vanillin, accompanied by increased Fe2+ levels, upregulated ACSL4 and KLF2, and downregulated GPX4. MDA-MB-231 cells were transfected with lentivirus containing si-KLF2 for 48 h or incubated with Fer-1 (an inhibitor of ferroptosis, 10 μM), followed by treated by 16 μM Vanillin for 24 h. Repressed cell viability, enhanced MDA and GSSG levels, declined GSH levels and SOD activities, increased Fe2+ levels, upregulated ACSL4, and downregulated GPX4 observed in Vanillin-treated MDA-MB-231 cells were significantly abolished by silencing KLF2 or Fer-1. Collectively, Vanillin suppressed proliferation of TNBC cells by inducing ferroptosis via mediating the KLF2/GPX4 axis.

[This corrects the article DOI: 10.3389/fimmu.2023.1175384.].

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility among women of reproductive age, yet the range of effective treatment options remains limited. Our previous study revealed that reduced levels of nicotinamide adenine dinucleotide (NAD+) in ovarian granulosa cells (GCs) of women with PCOS resulted in the accumulation of reactive oxygen species (ROS) and mitochondrial dysfunction. However, it is still uncertain whether increasing NAD+ levels in the ovaries could improve ovarian function in PCOS. In this study, we demonstrated that supplementation with the NAD+ precursor nicotinamide riboside (NR) prevented the decrease in ovarian NAD+ levels, normalized estrous cycle irregularities, and enhanced ovulation potential in dehydroepiandrosterone (DHEA)-induced PCOS mice. Moreover, NR supplementation alleviated ovarian fibrosis and enhanced mitochondrial function in ovarian stromal cells of PCOS mice. Furthermore, NR supplementation improved oocyte quality in PCOS mice, as evidenced by reduced abnormal mitochondrial clustering, enhanced mitochondrial membrane potential, decreased ROS levels, reduced spindle abnormality rates, and increased early embryonic development potential in fertilized oocytes. These findings suggest that supplementing with NAD+ precursors could be a promising therapeutic strategy for addressing ovarian infertility associated with PCOS. Ovarian NAD+ levels decreased in DHEA-induced PCOS mice, accompanied by mitochondrial dysfunction in oocytes and ovarian stromal cells, resulting in reduced oocyte quantity and quality, decreased early embryonic development potential, and increased ovarian fibrosis. After increasing ovarian NAD+ levels by NR supplementation to restore PCOS-related impairment of mitochondria function, ovarian dysfunction in PCOS was attenuated as characterized by improved oocyte quantity and quality, enhanced early embryonic development potential, and decreased ovarian fibrosis.

Autoantibodies, hallmark mediators of autoimmune diseases, drive pathogenesis through Fc receptors (FcRs) engagement. Among human FcRs, FcγRIIa is the most abundantly expressed subtype and plays a pivotal role in regulating both innate and adaptive immune responses. Genetic polymorphisms and dysregulated FcγRIIa signaling are increasingly implicated in autoimmune pathogenesis. By governing immune cell activation, differentiation, and effector functions, FcγRIIa emerges as a central orchestrator of immune responses. Recent clinical studies have identified FcγRIIa as a promising therapeutic target in patients with autoimmune diseases, as well as in murine autoimmune models. This review outlines the structure and cellular expression profile of FcγRIIa and elucidates its role in immune regulation. Furthermore, we discuss its association with autoimmune pathogenesis and highlight FcγRIIa targeted therapeutics evaluated in past and ongoing clinical trials for autoimmune disease treatment.

Autophagy is a cellular protective mechanism. As tumor cells are stimulated by drugs, autophagy is activated to increase their resistance to drugs. In gene regulation, microRNA (miRNA) plays a vital role. The diagnostic and prognostic potential of various miRNAs in cancer has been recognized, and for several years, miRNA-based therapeutic approaches have garnered significant interest in the oncology field. RAB10, a member of the RAB guanosine triphosphatase family, has been reported that it contributes to tumor resistance to chemotherapy. The bionanomaterial layered double hydroxide (LDH) is considered as an ideal gene delivery vehicle because of its nontoxicity, good biocompatibility, and slow drug release. According to our findings, we proved that miR-141-3p mediated breast cancer resistance to paclitaxel (PTX) by inhibiting autophagy through downregulation of RAB10, and LDH@miR-141-3p increased breast cancer cell sensitivity to PTX treatment, which provided a new idea for antitumor therapy.

Background:Breast cancer is one of the most common cancers among women. Tumor cell proliferation is highly dependent on aerobic glycolysis, so regulating aerobic glycolysis in breast cancer cells is a promising therapeutic strategy. Resveratrol (Res), as a potential new anti-breast cancer drug, has been shown to regulate the glycolysis of cancer cells and inhibit the metastasis and recurrence of breast cancer. The nano drug delivery system can regulate the aerobic glycolysis metabolism by targeting the signaling factors and reaction products of the tumor aerobic glycolysis process to enhance the anti-tumor effect. Methods:A new albumin-modified layered double hydroxide resveratrol dosage form (BSA@LDHs-Res) was synthesized by hydrothermal co-precipitation. Characterization was carried out to determine the successful synthesis of the nanocarrier system. The bioactivity, glycolytic activity and biocompatibility were examined by in vitro cellular assays; in vivo experiments were performed to further evaluate the anti-tumor effects of the BSA@LDHs-Res dosage form for breast cancer. Results:In this study, we obtained for the first time a bovine serum albumin-modified BSA@LDHs-Res loaded dosage form, which was able to enter breast cancer cells SKBR3 and MDA-MB-231 via endocytosis and successfully escaped from lysosomal capture. BSA@LDHs-Res inhibited the proliferation, migration, and invasion of two types of breast cancer cells, induced apoptosis, and promoted the reduction of mitochondrial membrane potential and ROS. BSA@LDHs-Res inhibited the expression and viability of the key enzymes of glycolysis, hexokinase 2 (HK2), pyruvate kinase (PK), and lactate dehydrogenase, resulting in decreased glucose consumption, decreased lactate accumulation, and decreased intracellular ATP levels. BSA@LDHs-Res was examined in the mouse model with good anti-tumor effects. Conclusion:BSA@LDHs-Res is an efficient nanoreagent for the treatment of breast cancer. The albumin-modified resveratrol layered double hydroxide delivery system developed in this study will provide some theoretical references for further research and clinical application of tumor aerobic glycolysis.

Rab Proteins, A Subfamily Of The Ras Superfamily Of Small Gtpases, Are Critical Regulators Of Intracellular Vesicular Trafficking, Which Is Intricately Linked To Various Cellular Processes. These Proteins Play Essential Roles Not Only In Maintaining Cellular Homeostasis But Also In Mediating The Complex Interplay Between Cancer Cells and Their Microenvironment. Rab Proteins Can Act As Either Oncogenic Factors Or Tumor Suppressors, With Their Functions Highly Dependent On The Cellular Context. Mechanistic Studies Have Revealed That Rab Proteins Are Involved In A Variety Of Processes, Including Vesicular Transport, Tumor Microenvironment Regulation, Autophagy, Drug Resistance, and Metabolic Regulation, and Play Either A Promotional Or Inhibitory Role In Cancer Development. Consequently, Targeting Rab Gtpases To Restore Dysregulated Vesicular Transport Systems May Offer A Promising Therapeutic Strategy To Inhibit Cancer Progression. However, It Is Equally Important To Consider The Potential Risks Of Disrupting Rab Functions, As Their Roles Are Highly Context-Dependent and May Have Opposing Effects In Different Malignancies. This Review Focuses On The Multifaceted Involvement Of Rab Family Proteins In Cancer Progression Underscores Their Importance As Potential Therapeutic Targets and Underscores The Need For A Deeper Understanding Of Their Complex Roles In Tumorigenesis.

Breast cancer has the highest incidence of female cancers globally and is a significant cause of death among female cancers. The field of breast cancer immunotherapy is rapidly evolving, offering new treatment options and hope to patients. Immune checkpoint inhibitors (ICBs) fight cancer by reprogramming the host immune system, leading a new paradigm in the treatment and application of specific types of breast cancer. While, si-RNA-based RNA interference technology shows great therapeutic potential as an alternative to immune checkpoint antibodies. This study confirmed the potential of si-NEAT1 to inhibit immune escape and epithelial mesenchymal transition (EMT) in breast cancer, which was mainly achieved by targeting PD-L1 through miR-141-3p. We employed LDH@si-NEAT1 to treat breast cancer cells and analyzed the effects of LDH@si-NEAT1-treated breast cancer cells on CD3 + CD8+ T cells and tumor-associated macrophages (TAMs) using co-culture technique. The results showed that LDH@si-NEAT1 activated CD3 + CD8+ T cells, thereby inhibiting the immune escape of breast cancer cells, as well as converting M2-type TAMs to M1-type TAMs, remodeling the immunosuppressive microenvironment of breast cancer mice while inhibiting EMT of breast cancer, and synergistically enhancing the immunotherapeutic effect of anti-PD-1. In conclusion, the present study emphasizes that LDH@si-NEAT1 can effectively reverse the immunosuppressive microenvironment of breast cancer and inhibit EMT of breast cancer, which provides a promising strategy for finding beneficial enhanced immunotherapy for breast cancer patients.

Breast cancer (BC) is the most prevalent and highly heterogeneous malignancy affecting females worldwide, and its development is closely linked to metabolic reprogramming. In this study, label-free quantification (LFQ) was used to analyze the protein expression in exosomes secreted by BC drug-resistant cells, identifying RAS-associated binding protein (RAB) 10 as the most significantly upregulated protein. RAB10, a member of the small GTPase family with complex biological functions, is highly expressed in BC and is associated with poor prognosis. In this study, we mainly utilized mouse breast cancer 4T-1 cells (wild-type control cells) and tumor-induced 4T-1 cells (isolated from mouse in situ tumor tissues to simulate the phenotype of the in vivo tumor microenvironment), and on this basis, conducted in vitro functional verification and in vivo tumorigenesis experiments. A comprehensive multi-omics analysis, including metabolomics and proteomics, following RAB10 knockdown, demonstrated the crucial role of RAB10 in regulating central carbon metabolism, which is essential for autophagy and ferroptosis in BC cells. Our study further confirmed that RAB10 mediates metabolic reprogramming in BC cells by regulating the Slc37a2/mTOR pathway, leading to enhanced autophagy and inhibition of ferroptosis. This comprehensive multi-omics analysis elucidated the key molecular and regulatory mechanisms underlying RAB10-induced metabolic reprogramming in tumors, providing potential new therapeutic targets and biomarkers for prognostic assessment in BC treatment.

Breast cancer is the most common type of cancer among women. It is well-established that microRNAs (miRNAs) play a critical role in cancer development by either degrading messenger RNA (mRNA) or inhibiting its translation, thereby suppressing the expression of specific genes. In this study, we found that the expression level of miR-142-3p was significantly lower in breast cancer cells and tissues than in normal breast epithelial cells and adjacent tissues. We demonstrated that miR-142-3p could inhibit the proliferation, migration, epithelial-mesenchymal transition (EMT), and stemness of MCF 7 breast cancer cells, while also promoting apoptosis. Further investigation revealed that miR-142-3p directly targets CXCL12 and regulates its expression. Silencing CXCL12 (using CXCL12 siRNA) suppressed the migration, EMT, and stemness of MCF 7 cells, and these effects were reversed by inhibition of miR-142-3p. Additionally, we observed alterations in β-catenin protein levels, suggesting that miR-142-3p may modulate the WNT/β-catenin signaling pathway through targeting CXCL12 in MCF 7 cells. Subsequent experiments indicated that miR-142-3p also plays a crucial role in overcoming paclitaxel resistance in MCF 7/PTX cells. SOX2 protein levels, which are associated with paclitaxel resistance, proliferation, migration, and EMT, were higher in MCF 7/PTX cells compared to MCF 7 cells. Overall, our findings suggest that miR-142-3p influences breast cancer progression by targeting the CXCL12/WNT/β-catenin pathway, thereby affecting cell migration, EMT, stemness, and paclitaxel resistance.

Recent studies have shown that disruptions in the nicotinamide adenine dinucleotide (NAD+) de novo synthesis pathway accelerate ovarian aging, yet its role in spermatogenesis remains largely unknown. In this study, we investigated the impact of the NAD+ de novo synthesis pathway on spermatogenesis by generating Qprt-deficient mice using CRISPR-Cas9 to target quinolinate phosphoribosyl transferase (Qprt), a key enzyme predominantly expressed in spermatocytes. Our results revealed that the deletion of Qprt did not affect NAD+ levels or spermatogenesis in the testes of 3-month-old mice. However, from 6 months of age onward, Qprt-deficient mice exhibited significantly reduced NAD+ levels in the testes compared to wild-type (WT) controls, along with a notable decrease in germ cell numbers and increased apoptosis. Additionally, these mice demonstrated mitochondrial dysfunction in spermatocytes, impaired progression through prophase I of meiosis, defective double-strand break (DSB) repair, and abnormal meiotic sex chromosome inactivation. Importantly, supplementation with the NAD+ precursor nicotinamide riboside (NR) in Qprt-deficient mice restored NAD+ levels and rescued the spermatogenic defects. These findings underscore the critical role of NAD+ de novo synthesis in maintaining NAD+ homeostasis and highlight its importance in meiotic recombination and meiotic sex chromosome inactivation in spermatogenesis.

Background:Metabolic reprogramming and immune evasion synergistically drive breast carcinogenesis, but their combined impact remains unclear. Methods:Transcriptomic data from the TCGA and GEO cohorts were integrated. Differentially expressed genes were identified, followed by WGCNA to detect immune-correlated co-expression modules. Immune-metabolism-related genes (IMGs) were screened using Genecards. Four machine learning algorithms (LASSO, SVM, RF, XGBoost) identified hub genes. The diagnostic value was evaluated by Kaplan-Meier and ROC analysis. CIBERSORT quantified immune microenvironment associations. The expression profiles of genes in different cells were plotted using single-cell RNA data. IHC validated protein expression in clinical samples. Results:Research has found that SELENOP and PKMYT1 are key immune metabolic hubs. Compared with normal tissues, the expression of SELENOP was significantly decreased (p < 0.05), while PKMYT1 showed an upward trend (p < 0.05). Both of these genes have demonstrated high accuracy in the diagnosis of breast cancer and can effectively predict the overall survival period of patients. Low SELENOP expression is associated with high PKMYT1 expression levels, which is significantly related to changes in immune infiltration and the expression patterns of checkpoint proteins. Immunohistochemical detection further confirmed that these genes were significantly correlated with histological grade, LAG-3, CD244, ER, PR and Her-2 and other indicators (p < 0.05). Conclusion:SELENOP and PKMYT1 are novel immunomodulatory factors related to multiple pathological indicators of breast cancer and can be used as diagnostic biomarkers.

A review of advancements in primordial follicle activation and cyclic recruitment research over the past 25 years is presented. The review examines the latest insights into the mechanisms of primordial follicle activation and the role of the ovarian Hippo signalling pathways, highlighting their potential for developing new infertility treatments. The concept of continuous waves of early antral follicles and their availability for cyclic recruitment is discussed. Several previously unresolved questions, such as the effect of steroid contraceptive pill usage on menopause timing, the potential risk for earlier menopause in mothers of dizygotic twins and the effects of repeated ovarian stimulation cycles on menopause onset are addressed. Controversies about the existence of female germ stem cells, the lifespan of follicles, the phenomenon of alternate ovulation between ovaries, potential changes in menopause onset in patients with polycystic ovary syndrome (PCOS) and endometriosis are discussed. In conclusion, future challenges in ovarian research, aiming to advance understanding and improve clinical practices in reproductive health are addressed.