Cancer is one of the primary causes of death worldwide, and its incidence continues to increase yearly. Despite significant advances in research, the search for effective and nontoxic preventive and therapeutic agents remains greatly important. Cancer is a multimodal disease, where various mechanisms play significant roles in its occurrence and progression. This highlights the need for multitargeted approaches that are not only safe and inexpensive but also provide effective alternatives for current therapeutic regimens. β-Sitosterol (SIT), the most abundant phytosterol found in various plant foods, represents such an option. Preclinical evidence over the past few decades has overwhelmingly shown that SIT exhibits multiple anticancer activities against varied cancers, such as liver, cervical, colon, stomach, breast, lung, pancreatic, and prostate cancers, in addition to leukemia, multiple myeloma, melanoma, and fibrosarcoma. In this article, we present the latest advances and perspectives on SIT-systematically summarizing its antitumor mechanisms of action into 7 main sections and combining current challenges and prospects-for its use as a promising agent for cancer prevention and treatment. In particular, SIT plays a role in cancer prevention and treatment mainly by enhancing apoptosis, inducing cell cycle arrest, bidirectionally regulating oxidative stress, improving metabolic reprogramming, inhibiting invasion and metastasis, modulating immunity and inflammation, and combating drug resistance. Although SIT holds such great promise, the poor aqueous solubility and bioavailability coupled with low targeting efficacy limit its therapeutic efficacy and clinical application. Further research on novel drug delivery systems may improve these deficiencies. Overall, through complex and pleiotropic mechanisms, SIT has good potential for tumor chemoprevention and chemotherapy. However, no clinical trials have yet proven this potential. This review provides theoretical basis and rationality for the further design and conduct of clinical trials to confirm the anticancer activity of SIT.

Purine, an abundant substrate in organisms, is a critical raw material for cell proliferation and an important factor for immune regulation. The purine de novo pathway and salvage pathway are tightly regulated by multiple enzymes, and dysfunction in these enzymes leads to excessive cell proliferation and immune imbalance that result in tumor progression. Maintaining the homeostasis of purine pools is an effective way to control cell growth and tumor evolution, and exploiting purine metabolism to suppress tumors suggests interesting directions for future research. In this review, we describe the process of purine metabolism and summarize the role and potential therapeutic effects of the major purine-metabolizing enzymes in ovarian cancer, including CD39, CD73, adenosine deaminase, adenylate kinase, hypoxanthine guanine phosphoribosyltransferase, inosine monophosphate dehydrogenase, purine nucleoside phosphorylase, dihydrofolate reductase and 5,10-methylenetetrahydrofolate reductase. Purinergic signaling is also described. We then provide an overview of the application of purine antimetabolites, comprising 6-thioguanine, 6-mercaptopurine, methotrexate, fludarabine and clopidogrel. Finally, we discuss the current challenges and future opportunities for targeting purine metabolism in the treatment-relevant cellular mechanisms of ovarian cancer.Graphical Abstract

Paeonol (Pae), a phenolic acid compound isolated from the Moutan Cortex, was previously demonstrated to exert multiple anticancer effects. The rational control of autophagy has been considered a potential treatment strategy for epithelial ovarian cancer. However, whether Pae induces autophagy and the relationship between its antitumour activities and autophagy in epithelial ovarian cancer are still unclear. In this study, we found that Pae induced not only antiproliferation activity and apoptosis but also autophagy, and complete autophagic flux was observed in A2780 and SKOV3 cells. In addition, combination treatment with Pae and an autophagy inhibitor (3-methyladenine and hydroxychloroquine) showed significant synergetic effects on inhibiting cell viability and promoting apoptosis in vitro and in the A2780 xenograft model, without severe side effects, which was often had by cisplatin. These results indicate that autophagy induced by Pae has a cytoprotective role in both A2780 and SKOV3 cells. Mechanistically, we found that Pae inhibited the protein kinase B(Akt)/mammalian target of rapamycin (mTOR) pathway. Furthermore, when combined with the inhibitors MK2206 and rapamycin to inhibit Akt and mTOR kinase activity, Pae-induced autophagy was increased. Taken together, our results demonstrate that Pae induced cytoprotective autophagy by inhibiting the Akt/mTOR pathway in ovarian cancer cells. Thus, the strategy of combining Pae with an autophagy inhibitor to block Akt/mTOR-dependent autophagy could enhance the antitumour activity of Pae and warrants further application for the treatment of ovarian cancer.

Tumor mutational burden (TMB) has been reported to determine the response to immunotherapy, thus affecting the patient’s prognosis in many cancers. However, it is unclear whether TMB or TMB-related signature could be used as prognostic indicators for ovarian cancer (OC), as its potential association with immune infiltration remains poorly understood. Therefore, this study aimed to develop a novel TMB-related risk model (TMBrisk) to predict the prognosis of OC patients on the basis of exploring TMB-related genes, and to explore the potential association between TMB/TMBrisk and immune infiltration. The mutational landscape, TMB scores, and correlations between TMB and clinical characteristics and immune infiltration were investigated in The Cancer Genome Atlas (TCGA)-OV cohort. Differentially expressed gene (DEG) analyses and weighted gene co-expression network analysis (WGCNA) were performed to derive TMB-related genes. TMBrisk was constructed by Cox regression and further validated in Gene Expression Omnibus (GEO) datasets. The mRNA and protein expression levels and biological functions of TMBrisk hub genes were verified through Gene Expression Profiling Interactive Analysis (GEPIA), GSCA Lite, the Human Protein Atlas (HPA) database, and RT-qPCR. TMBrisk-related biological phenotypes were analyzed in function enrichment and tumor immune infiltration signature. Potential therapeutic regimens were inferred utilizing the Genomics of Drug Sensitivity in Cancer (GDSC) database and connectivity map (CMap). According to our results, higher TMB was associated with better survival and higher CD8+ T cell, regulatory T cell, and NK cell infiltration. TMBrisk was developed based on CBWD1, ST7L, RFX5-AS1, C3orf38, LRFN1, LEMD1, and HMGB1. High TMBrisk was identified as a poor factor for prognosis in TCGA and GEO datasets; the high-TMBrisk group comprised more higher-grade (G2 and G3) and advanced clinical stage (stage III/IV) tumors. Meanwhile, higher TMBrisk was associated with an immunosuppressive phenotype, with less infiltration of a majority of immunocytes and less expression of several genes of the human leukocyte antigen (HLA) family. Moreover, a nomogram containing TMBrisk showed a strong predictive ability demonstrated by time-dependent ROC analysis. Overall, this novel TMB-related risk model (TMBrisk) could predict prognosis, evaluate immune infiltration, and discover new therapeutic regimens in OC, which is very promising in clinical promotion.

Introduction: Ovarian cancer (OC) is one of the major diseases threatening women's health and life. Estimating the burden trends and risk factors of OC can help develop effective management and prevention measures. However, there is a lack of comprehensive analysis concerning the burden and risk factors of OC in China. In this study, we aimed to assess and predict the burden trends of OC in China from 1990 to 2030, and make a comparison with the global level.Methods: We extracted prevalence, incidence, mortality, disability-adjusted life years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs) data from the Global Burden of Disease Study 2019 (GBD 2019) and characterized OC burden in China by year and age. OC epidemiological characteristics were interpreted by conducting joinpoint and Bayesian age-period-cohort analysis. We also described risk factors, and predicted OC burden from 2019 to 2030 using Bayesian age-period-cohort model.Results: In China, there were about 196,000 cases, 45,000 new cases and 29,000 deaths owing to OC in 2019. The age-standardized rates (ASRs) of prevalence, incidence and mortality have increased by 105.98%, 79.19%, and 58.93% respectively by 1990. In the next decade, OC burden in China will continue to rise with a higher rate than the global level. The OC burden in women under 20 years of age is slowing down, while the burden in women over 40 years of age is getting more severe, especially in postmenopausal and older women. High fasting plasma glucose is the major factor contributing the most to OC burden in China, and high body-mass index has surpassed occupational exposure to asbestos to be the second risk factor. OC burden from 2016 to 2019 in China has increased faster than ever before, indicates an urgent need to develop effective interventions.Conclusion: The burden of OC in China has shown an obvious upward trend in the past 30 years, and the increase rate accelerated significantly in recent 5 years. In the next decade, OC burden in China will continue to rise with a higher rate than the global level. Popularizing screening methods, optimizing the quality of clinical diagnosis and treatment, and promoting healthy lifestyle are critical measures to improve this problem.

Bioactive peptides and proteins (BAPPs) are promising therapeutic agents for tissue repair with considerable advantages, including multifunctionality, specificity, biocompatibility, and biodegradability. However, the high complexity of tissue microenvironments and their inherent deficiencies such as short half-live and susceptibility to enzymatic degradation, adversely affect their therapeutic efficacy and clinical applications. Investigating the fundamental mechanisms by which BAPPs modulate the microenvironment and developing rational delivery strategies are essential for optimizing their administration in distinct tissue repairs and facilitating clinical translation. This review initially focuses on the mechanisms through which BAPPs influence the microenvironment for tissue repair via reactive oxygen species, blood and lymphatic vessels, immune cells, and repair cells. Then, a variety of delivery platforms, including scaffolds and hydrogels, electrospun fibers, surface coatings, assisted particles, nanotubes, two-dimensional nanomaterials, and nanoparticles engineered cells, are summarized to incorporate BAPPs for effective tissue repair, modification strategies aimed at enhancing loading efficiencies and release kinetics are also reviewed. Additionally, the delivery of BAPPs can be precisely regulated by endogenous stimuli (glucose, reactive oxygen species, enzymes, pH) or exogenous stimuli (ultrasound, heat, light, magnetic field, and electric field) to achieve on-demand release tailored for specific tissue repair needs. Furthermore, this review focuses on the clinical potential of BAPPs in facilitating tissue repair across various types, including bone, cartilage, intervertebral discs, muscle, tendons, periodontal tissues, skin, myocardium, nervous system (encompassing brain, spinal cord, and peripheral nerve), endometrium, as well as ear and ocular tissue. Finally, current challenges and prospects are discussed.