Up-Regulation

KMT2C and KMT2D, encoding histone H3 lysine 4 methyltransferases, are among the most commonly mutated genes in triple-negative breast cancer (TNBC). However, how these mutations may shape epigenomic and transcriptomic landscapes to promote tumorigenesis is largely unknown. Here we describe that deletion of Kmt2c or Kmt2d in non-metastatic murine models of TNBC drives metastasis, especially to the brain. Global chromatin profiling and chromatin immunoprecipitation followed by sequencing revealed altered H3K4me1, H3K27ac and H3K27me3 chromatin marks in knockout cells and demonstrated enhanced binding of the H3K27me3 lysine demethylase KDM6A, which significantly correlated with gene expression. We identified Mmp3 as being commonly upregulated via epigenetic mechanisms in both knockout models. Consistent with these findings, samples from patients with KMT2C-mutant TNBC have higher MMP3 levels. Downregulation or pharmacological inhibition of KDM6A diminished Mmp3 upregulation induced by the loss of histone-lysine N-methyltransferase 2 (KMT2) and prevented brain metastasis similar to direct downregulation of Mmp3. Taken together, we identified the KDM6A-matrix metalloproteinase 3 axis as a key mediator of KMT2C/D loss-driven metastasis in TNBC.

In recent years, immunotherapy, particularly PD-1 antibodies, have significantly enhanced the outcome of gastric cancer patients. Despite these advances, some patients do not respond well to treatment, highlighting the need to understand resistance mechanisms and develop predictive markers of treatment effectiveness. This study retrospectively analyzed data from 106 patients with stage IV gastric cancer who were treated with first-line immunotherapy in combination with chemotherapy. By comparing plasma cytokine levels between patients resistant and sensitive to PD-1 antibody therapy, the researchers identified elevated IL-4 expression in the resistant patients. Mechanical investigations revealed that IL-4 induces metabolic changes in macrophages that activate the PI3K/AKT/mTOR pathway. This alteration promotes ATP production, enhances glycolysis, increases lactic acid production, and upregulates FcγRIIB expression in macrophages. Ultimately, these changes lead to CD8+ T cell dysfunction and resistance to PD-1 antibody therapy in gastric cancer. These findings highlight the role of IL-4-induced macrophage polarization and metabolic reprogramming in immune resistance and verify IL-4 as potential targets for improving treatment outcomes in gastric cancer patients.

BackgroundFerroptosis, a novel iron-ion-dependent metabolic cell death mode with lipid peroxides as the main driving substrate, plays an irreplaceable role in the development and preventive treatment of hepatocellular carcinoma. Curcumin has potent pharmacological anti-tumor effects.Aim of the studyWe aimed to evaluate the ex vivo and in vivo cancer inhibitory activity of curcumin and its specific mechanism of action.Materials and methodsWe used the hepatocellular carcinoma cell lines HepG2 and SMMC7721 to assess the direct inhibition of hepatocellular carcinoma proliferation by curcumin in vitro and a tumor xenograft model to evaluate the in vivo cancer inhibitory effect of curcumin.ResultsIn this study, we found that ferroptosis's inhibitors specifically reversed the curcumin-induced cell death pattern in HCC. After curcumin intervention, there was a substantial increase in MDA levels and iron ion levels, and a decrease in intracellular GSH levels. Meanwhile, the expression of GPX4 and SLC7A11 was significantly reduced at the protein levels, while ACSL4 and PTGS2 expression was significantly increased.ConclusionsThis study showed that curcumin significantly decreased the proliferation of HCC cells and significantly increased the sensitivity of ferroptosis. These results suggest that ACSL4 is a viable target for curcumin-induced ferroptosis in treating HCC.

B7-H3 (CD276) is an immune checkpoint co-signaling molecule expressed on immune and non-immune cells. It is best known for suppressing T-cell responses but can also promote inflammation depending on the microenvironment. In neuroinflammatory models such as experimental autoimmune encephalomyelitis, B7-H3 expression increases concomitantly with the inflammatory response, and its inhibition is associated with reduced disease progression. Although its role in ischemic stroke remains unclear, we hypothesized that cerebral ischemia/reperfusion (I/R) would upregulate B7-H3 expression in the ischemic brain and that increased B7-H3 expression would positively correlate with pro-inflammatory cytokine expression. Young and aged male and female rodents, including normotensive and spontaneously hypertensive rats to model comorbid hypertension, underwent transient middle cerebral artery occlusion (MCAO) followed by reperfusion. Brain tissue was collected on post-MCAO days 1, 3, 5, or 7. B7-H3 mRNA was analyzed by real-time PCR, whereas protein expression was assessed by Western blotting and immunohistochemistry at selected time points. B7-H3 expression was significantly upregulated in the ischemic brain across sexes, age groups, and species. The extent of B7-H3 degradation was influenced by species, sex, age, and time after cerebral I/R. Upregulation of B7-H3 was observed at both the mRNA and protein levels and was localized primarily to the somatosensory cortex and caudate putamen in the ipsilateral (ischemic) hemisphere, the main regions affected in this MCAO model. Elevated B7-H3 expression in the ischemic brain positively correlated with the pro-inflammatory mediator TNFα. In rats, the temporal profile of B7-H3 expression paralleled the early inflammatory phase associated with secondary tissue damage after ischemic stroke. These findings identify B7-H3 as an ischemia-induced immune checkpoint molecule in the brain that may modulate post-stroke immune responses and support further investigation into its beneficial versus detrimental roles in neuroinflammation and its potential as a therapeutic target following cerebral I/R.