Tumor cell plasticity and stemness fuel treatment resistance and cancer evolution into often incurable, metastatic terminal disease. To better understand these fundamental aspects of tumorigenesis, here we examine a potential role of KCNMA1, a calcium-activated potassium channel that impacts cell (patho)physiology through membrane functions, in regulating ovarian cancer cell behavior, including plasticity, proliferation, mobility, and response to treatment. Pharmacological activation of KCNMA1 promoted differentiation, while channel blocking induced dedifferentiation and enhanced dissemination potential. Cyclical activation and inhibition potentiated the epithelial/mesenchymal hybrid cell state prone to stemness. KCNMA1 overexpression combined with low-dose channel blockade supported three-dimensional tumor growth. Mechanistically, we found that the balance between cytosolic calcium and potassium, in addition to their absolute levels, governed the observed changes. Our findings support a model in which KCNMA1-mediated regulation of potassium buffers fluctuating calcium signals that drive phenotypic plasticity, thereby stabilizing the epithelial/mesenchymal hybrid state. In addition, KCNMA1 modulation sensitized ovarian cancer cells to standard-of-care chemotherapeutics. Together, this work provides new insights into the role of KCNMA1 and calcium/potassium homeostasis in ovarian cancer cell adaptability, with implications for treatment.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) deposition, neuroinflammation, and cognitive decline. Microglia, the brain's primary immune cells, play a central role in AD pathogenesis by driving neuroinflammatory responses. Deubiquitinating enzymes (DUBs) regulate microglial activation, but the role of the ovarian tumor domain-containing DUB OTUD6A in AD remains unclear. In this study, we demonstrate that OTUD6A is upregulated in microglia across multiple AD models, including Aβ-infused mice, 3×Tg mice, and APP/PS1 mice. Otud6a KO or microglia-specific knockdown Otud6a ameliorated cognitive deficits and reduced neuroinflammation in AD mice. Besides, OTUD6A binds to C/EBPβ by removing K48-linked ubiquitin chains at lysine 253 (K253), thereby leading to C/EBPβ accumulation and enhancing NF-κB signaling and proinflammatory cytokine production. Moreover, mutation of OTUD6A catalytic residue (C157A) abolished its deubiquitination activity, confirming its role in C/EBPβ stabilization. Furthermore, C/EBPβ knockdown reversed OTUD6A-mediated neuroinflammation, validating the microglial OTUD6A-C/EBPβ-NF-κB axis as a critical pathway in AD pathogenesis. Therefore, our findings highlight OTUD6A as a novel regulator of microglial activation and suggest that targeting this DUB could provide a therapeutic strategy to mitigate neuroinflammation in AD.

Innate immune cells constitute the majority of the tumor microenvironment (TME) and mediate anti-tumor immunity and immunotherapy responses. While single-cell T and B cell receptor sequencing have revealed insights into the clonal dynamics of adaptive immunity, the lack of analogous tools has precluded similar analysis of innate immune cells. Here, we describe a method leveraging somatic mitochondrial DNA (mtDNA) mutations to reconstruct clonal lineage relationships between cells in native human tissues. By jointly profiling single-cell chromatin accessibility and mtDNA variants, we resolve clonal dynamics of 218,715 cells from matched tumors, tissues, and blood from patients with lung and ovarian cancers. Clonal tracing reveals that TME-resident myeloid subsets, including macrophages and type 3 dendritic cells (DC3), are clonally related to circulating and tissue-infiltrating monocytes. We further identify distinct DC-biased and macrophage-biased clones, whose circulating monocyte precursors exhibit distinct epigenetic profiles, suggesting intratumoral myeloid differentiation fate may be peripherally programmed before TME infiltration.

Predicting lung cancer risk would enhance prevention trials. Although the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial demonstrated reduced lung cancer incidence with interleukin (IL)-1β inhibition, the high number needed to treat (NNT) to prevent lung cancer limits its use in unselected populations. Using machine learning, we identified a 14-protein plasma signature predicting lung cancer more than 5 years before diagnosis. The signature, validated across eight cohorts, was elevated in current smokers and individuals exposed to particulate matter (PM) and linked to lung myeloid and alveolar cells. In epidermal growth factor receptor (EGFR)-driven lung adenocarcinoma, diverse epithelial lineages converged on a keratin8+/claudin4+ alveolar transitional state (KAC), whose transcriptional programs correlated with signature emergence. Components of the signature were induced by PM, oncogenic EGFR, or IL-1β, whereas IL-1β inhibition restrained PM-driven KAC expansion and early tumorigenesis. In CANTOS, the signature identified individuals who seemed to benefit more from anti-IL-1β therapy, lowering the NNT threshold and nominating circulating signals of tumor promotion for prevention.

Long non-coding RNAs (lncRNAs) are involved in the development and progression of ovarian cancer (OC). Super-enhancers play vital roles in epigenomic regulation. We investigated the functions and mechanisms of the super-enhancer-driven OC-specific lncRNA ITGB2-AS1. In this study, we revealed that the lncRNA ITGB2-AS1 was abnormally expressed in OC tissues and cells and was associated with poor prognosis. In vitro, ITGB2-AS1 silencing attenuated the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of SKOV3 and A2780 cells, whereas ITGB2-AS1 overexpression showed the opposite effect. ITGB2-AS1 inhibition in SKOV3 cells reduced tumor growth and EMT progression in vivo. Further analysis revealed that the transcription factor TFAP2C acts on a specific super-enhancer and drives ITGB2-AS1 to activate transcription. `ITGB2-AS1 directly binds to IQGAP1 protein, positively regulates its expression, and activates the canonical Wnt/β-catenin signaling pathway. The TFAP2C / ITGB2-AS1 / IQGAP1 / β-catenin axis may be a potential target for OC treatment.

Ovarian cancer (OC) is among the most prevalent malignant tumors of the female reproductive system. Its high mortality rate is strongly associated with the development of chemotherapy resistance, making research into resistance mechanisms critical for improving patient outcomes. In recent years, ferroptosis, an iron-dependent form of cell death, has garnered significant attention in tumor resistance research due to its unique regulatory mechanisms. Studies indicate that ferroptosis contributes to OC resistance by modulating pathways including lipid peroxidation, iron metabolism, and antioxidant systems; however, its precise molecular mechanisms remain incompletely elucidated. Furthermore, the interaction between ferroptosis and resistance to conventional chemotherapy agents in OC has emerged as a research hotspot. This systematic review examines the fundamental characteristics of ferroptosis and its potential mechanisms in OC resistance, while exploring therapeutic strategies targeting ferroptosis-related pathways to reverse drug resistance. By synthesizing existing research advances, this paper aims to provide new theoretical foundations to deepen our understanding of OC resistance mechanisms and to suggest potential directions for developing novel targeted therapeutic approaches.

As colorectal cancer survival improves, survivors face an increased risk of subsequent primary cancers (SPCs). This systematic review assessed associations between cancer treatments, tumor features and other risk factors and the risk of SPCs for colorectal cancer survivors. We searched four databases for peer reviewed articles published up to October 2025. We conducted meta analyses using random effects models to summarize pooled relative risks (RRs) for each SPC. Of 10,577 articles screened, 36 met the inclusion criteria. Radiotherapy was associated with increased risks of uterine (RR 2.65; 95% confidence interval [CI] 1.63-3.67), ovarian (RR 2.26, 95%CI 1.30-3.91), urethral (RR 4.66, 95%CI 1.96-11.06) and lung cancer (RR 1.19, 95%CI 1.04-1.35) but a decreased risk of prostate cancer (RR 0.55, 95%CI 0.47-0.64). In women, chemotherapy was associated with increased risks of uterine (RR 2.26, 95%CI 1.63-3.15) and breast cancer (RR 1.22, 95%CI 1.05-1.43). Colon (vs rectal) and proximal colon (vs distal) cancers were associated with higher SPC risk, whereas stage II/III (vs stage I) was associated with lower SPC risk. Older age, male sex, White race (vs Black/Asian), smoking, alcohol use and metabolic comorbidities were associated with increased SPC risk. These findings support the need for risk based surveillance after colorectal cancer.

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic and multi-spectrum disease, characterized by the development of benign hamartomas in multiple organ systems, which may be misdiagnosed as malignant neoplasms. We present the case of a TSC patient with a large ovarian endometrioma that showed heterogeneous enhancement on a computerized tomography (CT) scan, and Tc-99 m-methylene diphosphonate (99mTc-MDP) bone scintigraphy revealed the possibility of bone metastases. She was initially misdiagnosed with a malignant ovarian tumor and multiple metastases, whereas the definitive diagnosis was established based on clinical diagnostic criteria related to TSC. Following multidisciplinary management, our patient's general condition remains satisfactory. We aim to enhance the understanding of TSC by summarizing the clinical manifestations and imaging findings of our patient in order to reduce the rates of missed and misdiagnosed cases.