Lirong Xiao

Uveal melanoma (UM) represents an uncommon intraocular malignancy with high aggressiveness. Dysregulation of ferroptosis has been associated with UM progression. Dihydroartemisinin (DHA), a natural derivative of Artemisia annua, exhibits potent antitumor activity with a favorable safety profile, yet its role in ferroptosis regulation in UM remains unclear. Here, we showed that DHA significantly reduced the proliferation and invasiveness of UM cells—both primary and secondary—with effects intensifying over time and dose. Transcriptomic analysis indicated that DHA may exert antitumor effects by modulating the ferroptosis-related pathway, characterized by upregulating heme oxygenase-1 (HO-1) and downregulating the SLC7A11 (xCT)/GPX4 axis, leading to iron accumulation, increased ROS and lipid peroxidation, and mitochondrial dysfunction. Iron chelators and pancaspase inhibitors partially reverse these effects, whereas HO-1 inducers enhance them. Overall, our results suggest that DHA suppresses UM progression by inducing ferroptosis and mitochondrial dysfunction, while the HO-1 and xCT/GPX4 pathways may contribute to these effects. DHA may represent a potential therapeutic approach for UM, warranting further investigation.

Von Hippel–Lindau (Vhl) protein inhibits hypoxia-inducible factor (Hif), yet its deletion in murine retina does not cause the extensive angiogenesis expected with Hif induction. The mechanism is unclear. Here we show that retinoblastoma tumor suppressor (Rb1) constrains expression of Hif target genes in the Vhl ^–/– retina. Deleting Rb1 induced extensive retinal neovascularization and autophagic ablation of photoreceptors in the Vhl ^–/– retina. RNA-sequencing, ChIP, and reporter assays showed Rb1 recruitment to and repression of certain Hif target genes. Activating Rb1 by deleting cyclin D1 induced a partial defect in the retinal superficial vascular plexus. Unexpectedly, removing Vhl suppressed retinoblastoma formation in murine Rb1/Rbl1 –deficient retina but generated subretinal vascular growths resembling retinal angiomatous proliferation (RAP) and retinal capillary hemangioblastoma (RCH). Most stromal cells in the RAP/RCH–like lesions were Sox9 ⁺ , suggesting a Müller glia origin, and expressed Lgals3, a marker of human brain hemangioblastoma. Thus, the Rb family limit Hif target gene expression in the Vhl ^–/– retina, and removing this inhibitory signal generates new models for RAP and RCH.

Purpose To determine whether the GNAQ/11 mutation correlated with the outcome of patients with uveal melanoma (UM) when genetic heterogeneity was considered. Methods We performed a retrospective study of sixty-seven patients with UM. The heterogeneity of GNAQ/11 was examined by using droplet digital PCR. The correlation between metastasis and heterogeneity of the GNAQ/11 mutation was analysed. Disease free survival curves were constructed using the Kaplan-Meier method, and the Wilcoxon log-rank test was used to compare the curves. Results The GNAQ/11 mutation ratio was varied between each case. Among these patients, 28.35% of them harboured homogeneous mutation of GNAQ/11, 62.69% present heterogeneous mutation and 8.96% didn’t present either GNAQ or GNA11 mutation. The tumour with heterogeneous mutation of GNAQ/11 has a higher metastatic rate than that with homogeneous mutation (13/29 vs 1/18, p=0.027). In Kaplan-Meier analysis, metastasis-free survival was not significantly associated with either homogeneous or heterogeneous mutation of GNAQ/11. Conclusion The mutation ratio of GNAQ/11 in UM was quite variable. The tumour with heterogeneous mutation of GNAQ/11 is more likely to develop a poor prognosis than that with homogeneous mutation of GNAQ/11.