Background: 5‐Fluorouracil (5‐FU) and capecitabine‐associated cardiotoxicity ranging from asymptomatic electrocardiography (ECG) abnormalities to severe myocardial infarction has been reported in a number of studies, but such cardiotoxicity in Chinese patients with malignant diseases has not been investigated to date. In the present study, we aimed to prospectively evaluate the incidence rates and clinical manifestations of 5‐FU‐ and capecitabine‐associated cardiotoxicity in cancer patients recruited from multiple centers in China. Methods: Among the 527 patients who completed the study, 196 received 5‐FU‐based chemotherapy and 331 received capecitabine‐based chemotherapy as either first‐line or adjuvant therapy. Adverse events were reported during the treatment and up to 28 days of follow‐up. Outcome measures included ECG, myocardial enzymes, cardiac troponin, brain natriuretic peptide and echocardiography. Univariate analysis and logistic regression were performed for subgroup analysis and identification of significant independent variables that are associated with cardiotoxicity of both agents. Results: In total, 161 of 527 patients (30.6%) experienced cardiotoxicity. The incidence rate of cardiotoxicity was 33.8% (112/331) in the capecitabine group, which was significantly higher than the rate of 25% (49/196) in the 5‐FU group ( P = 0.0042). 110/527 patients (20.9%) suffered arrhythmia, 105/527 (19.9%) developed ischemic changes, while only 20/527 patients (3.8%) presented heart failure and 6/527 patients (1.1%) had myocardial infarction. Pre‐existing cardiac disease, hypertension, capecitabine‐based chemotherapy and duration of treatment were identified as significant risk factors associated with cardiotoxicity. The odds ratio were 15.7 (prior history of cardiac disease versus no history), 1.86 (capecitabine versus 5‐FU), 1.06 (5–8 versus 1–4 chemotherapy cycles) and 1.58 (hypertension versus no hypertension), respectively. Conclusions: Cardiotoxicity induced by fluoropyrimidines in the Chinese population may be underestimated in clinical practice. Close monitoring of patients is recommended, especially for those patients at high risk for cardiotoxicity. Possible risk factors are duration of treatment, capecitabine‐based chemotherapy, pre‐existing cardiac diseases and hypertension. Trial registration This study was initiated on January 22, 2014 and has been retrospectively registered with the registration number ChiCTR1800015434

The accumulation of regulatory T cells (Tregs) in the tumor microenvironment is a key factor for immunosuppression and immune escape of cancer cells. Genistein is a natural isoflavonoid in soybeans, possessing a wide range of pharmacological bioactivities. However, the immunomodulatory potential of genistein remains largely unexplored. This study investigated the synergistic efficacy of genistein with anti-PD-1 therapy in a mouse model of melanoma. The regulatory role of genistein in Treg differentiation and functional stability was also examined in this study. The antitumor effects of genistein, alone or in combination with anti-PD-1 therapy, were evaluated in the mouse B16-F10 melanoma model. The profiles of intratumoral Tregs and CD8 ⁺ cytotoxic T cells were profiled using flow cytometry. The impact of genistein on the suppressive function and differentiation of Tregs was also studied in vitro. RT-qPCR, Western blotting and flow cytometry were conducted to characterize the functional phenotype of Tregs under genistein treatment. Genistein showed a synergistic effect with anti-PD-1 therapy in B16-F10 melanoma models, achieving enhanced immune infiltration and functional reprogramming of the tumor microenvironment. This combinatorial strategy not only reduced intratumoral Tregs but also elevated the CD8 ⁺ /Treg ratio. At the mechanistic level, genistein effectively suppressed critical Treg surface markers, which are indispensable for Treg-mediated immunosuppression. Furthermore, it disrupted Treg differentiation by attenuating PI3K/AKT signaling phosphorylation. Our data demonstrated that genistein boosts the antitumor effect of anti-PD-1 therapy by impairing the immunosuppressive function and differentiation of Tregs, indicating that genistein has the potential to enhance the treatment outcome of the immune checkpoint inhibitor.

Protein monoaminylation represents a new layer of neural–cancer regulation, but its role in gastric tumorigenesis is not understood. Using untargeted plasma metabolomics, we revealed that the level of serotonin (5-HT) is significantly elevated in gastric cancer (GC) patients. Functionally, 5-HT treatment dramatically promoted GC cell proliferation and tumor growth in a dose-dependent manner. Importantly, this oncogenic effect was abrogated by the inhibition of transglutaminase 2 (TGM2), indicating a crucial role for protein serotonylation via a receptor-independent mechanism. Using a 5-HT-based chemoproteomic probe, we identified a broad spectrum of serotonylation targets, including key ferroptosis-related proteins such as glutathione peroxidase 4 (GPX4). Specifically, we found that GPX4 is serotonylated by TGM2 at residues Gln55 and Gln77, which increases GPX4 protein stability by attenuating its ubiquitin-mediated degradation, thereby conferring resistance to ferroptosis and facilitating tumor growth. Clinically, TGM2 levels were positively correlated with tumoral GPX4 expression in GC patient specimens. Collectively, our results establish TGM2-mediated GPX4 serotonylation as a key mechanism driving GC progression through ferroptosis resistance, highlighting its potential as both a diagnostic biomarker and a therapeutic target within the neural–tumor axis.

Background: DICER is a key RNase III enzyme that cleaves processes miRNAs into their mature form. It is remarkably down-regulated in most epithelial ovarian cancer (EOC) and the down-regulation is associated with high grade malignancy as well as poor clinical outcomes. In this study, we aimed to discover a lncRNA interacting with DICER to participate in the process of microRNAs maturation and as a result promoting development of EOC. Methods: We conducted a RIP-seq aimed at DICER and we obtained its chromosomal location by aligning the sequence in PubMed. And the lncRNA was named DATOC-1 (DICER Associated Transcript 1 in Ovarian Cancer). We tested relative expression of DATOC-1 in 53 EOC and 7 adjacent ovarian samples by qRT-PCR. Then the expression in EOC patients derived from The Cancer Genome Atlas (TCGA) were analysed to identify DATOC-1-based signatures for EOC prognosis with survival analysis. Lastly, shRNA Screening and lentiviral transduction was used to determine the function of DATOC-1 in vitro and in vivo. Results: We identified the lncRNA RP5-1120P11.1 as DATOC-1, which highly expressed in EOC tissues than in adjacent. And Kaplan-Meier analysis indicated that the patients with EOC that expressed high levels of DATOC-1 had a worse prognosis and shorter disease OS compared with DATOC-1 low-expressed patients. In addition, DATOC-1 were further identified participating in EOC cell proliferation, cell cycle regulation and cell invasion. And knockdown of DATOC-1 inhibits tumor progression in vivo. Furthermore, knockdown of DATOC-1 increased the expression of miR7. The evidence showed that miR7 functioning as a tumor suppressor gene in EOC. Conclusions: Our research shows that DATOC-1 can inhibit the development of EOC and is a promising therapeutic target.

The Hedgehog (Hh) signaling pathway plays an essential role in embryonic development, and its aberrant activation is associated with pancreatic cancer progression. However, the function of Suppressor of Fused (SUFU), a critical negative regulator of the Hh pathway, in pancreatic cancer has been poorly studied. In this study, we found that SUFU knockdown significantly inhibits pancreatic cancer cell growth, migration, and proliferation while inducing apoptosis. We identified a direct interaction between JOSD1 and SUFU, whereby JOSD1 stabilizes SUFU protein by inhibiting its ubiquitination and proteasomal degradation. Public database analyses revealed a positive correlation between JOSD1 and SUFU expression in pancreatic cancer tissues, and immunofluorescence staining of clinical samples further showed that JOSD1 and SUFU are co-localized and expressed at higher levels in pancreatic cancer tissues compared with normal pancreatic tissues. Notably, SUFU regulates pancreatic cancer cell behavior through a non-canonical, Hh-independent mechanism. Depletion of either JOSD1 or SUFU downregulated proliferation-related genes and upregulated apoptosis-related genes, thereby suppressing pancreatic cancer cell growth and promoting apoptosis, with these effects reversed by SUFU restoration. Consistently, silencing of JOSD1 or SUFU significantly attenuates tumor growth and reduces Ki67 expression in vivo, whereas re-expression of SUFU in JOSD1-deficient tumors restores tumor growth and proliferation. Collectively, these findings highlight the functional importance of JOSD1-mediated SUFU stabilization in pancreatic cancer and suggest potential therapeutic strategies targeting this axis.