Liu Chen

Radiotherapy (RT) stands as the primary treatment for tumors, but it inevitably causes damage to normal cells. Consequently, radiation injury is a crucial consideration for radiation oncologists during therapy planning. Cell death including apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis play significant roles in tumor treatment. While previous studies elucidated the induction of apoptosis and autophagy by ionizing radiation (IR), recent attention has shifted to pyroptosis, ferroptosis, and necroptosis, revealing their effects induced by IR. This review aims to summarize the strategies employed by IR, either alone or in combination therapy, to induce pyroptosis, ferroptosis, and necroptosis in radiation injury. Furthermore, we explore their effects and molecular pathways, shedding light on their roles in radiation injury. Finally, we summarize the regulative agents for these three types of cell death and their mechanisms. In summary, optimizing radiation dose, dose rate, and combined treatment plans to minimize radiation damage and enhance the killing effect of RT is a key focus.

• We first identified the anti-liver fibrosis effect of OAG. • Atg5 deficiencies in hepatocytes aggravated liver fibrosis, while OAG prevents mice fibrosis dependent on hepatic Atg5 . • OAG induced autophagy via AMPK-ULK1 pathway in hepatocytes with the PPARγ regulation. • OAG inhibited HSC activation through decreasing IL-6 release of hepatocyte. Hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality, is closely linked to liver fibrosis, yet effective preventive therapies remain elusive. Autophagy is a critical cellular process that maintains hepatic homeostasis, and its disruption is implicated in the progression of fibrosis and HCC. This study aimed to evaluate the efficacy of oroxyloside (OAG), a flavonoid derived from Scutellaria baicalensis , in preventing liver fibrosis associated with cancer. Mouse models of liver fibrosis and hepatocarcinogenesis were developed using carbon tetrachloride (CCl 4 ) alone or a combined with diethylnitrosamine (DEN), with or without OAG treatment. Hepatocyte-specific Atg5 knockout mice (Atg5 Hep-/− ) and in vitro models with silenced Atg5 or PPARγ were used to investigate autophagy's role in OAG's therapeutic effects. To analyze the correlation between autophagy and hepatic fibrosis or cancer we use the TCGA and GSE database. Patient tissue samples (79 pairs) associated HCC was investigated by immunohistochemistry. This study demonstrates that OAG restores autophagic flux through the AMPK-ULK1 pathway in a PPARγ-dependent manner, reducing oxidative stress, DNA damage, and inflammatory cytokine IL-6 production. These mechanisms culminate in the inhibiting the activation of hepatic stellate cell activation and fibrosis progression. OAG also significantly attenuated liver tumor burden and improved survival in a chronic liver injury model. Importantly, the therapeutic effects of OAG were diminished in Atg5-deficient hepatocytes, highlighting its reliance on autophagy. This mechanistic insight differentiates OAG from existing anti-fibrotic or HCC therapies by targeting the interplay between autophagy and inflammation. OAG represents an innovative therapeutic approach to liver fibrosis and HCC, acting through autophagy-dependent pathways to inhibit inflammation and oxidative stress. Its dual anti-fibrotic and anti-carcinogenic effects position OAG as a promising candidate for addressing the unmet clinical needs in chronic liver disease.

Introduction Advanced hepatocellular carcinoma (HCC) poses significant therapeutic challenges due to chemotherapy resistance and limited efficacy of current targeted therapies. To address this unmet need, we developed a bispecific antibody (BsAb) platform targeting CD16A on natural killer (NK) cells and glypican-3 (GPC3), a tumor-specific antigen overexpressed in 70% of HCC cases. Methods High-affinity anti-CD16A single-chain variable fragments (scFvs) were selected via phage display, followed by engineering of Fc-stabilized BsAbs (MA4-hFc(N297A)-CD16A series) to minimize FcγR-mediated toxicity. Functional validation included binding kinetics (ELISA, flow cytometry, and fluorescence co-localization analysis), in vitro cytotoxicity assays (luciferase-based killing), and in vivo efficacy studies in Huh7 xenograft models. Synergy with sorafenib was assessed using CompuSyn analysis. Results The lead candidate, MA4-hFc-CD16AM19, exhibited nanomolar affinity (EC50 < 10 nM for human CD16A) with no murine cross-reactivity. It demonstrated potent, dose-dependent cytotoxicity against GPC3+ HCC lines (HepG2/Huh7/Hep3B, IC50 = 15–35 ng/mL) via NK cell activation, surpassing conventional antibody-dependent cellular cytotoxicity (ADCC). Combined with sorafenib, MA4-hFc-CD16AM19 achieved synergistic tumor suppression (CI=0.41). In vivo , BsAb treatment (5 mg/kg) significantly inhibited tumor growth in xenograft models, correlating with enhanced intratumoral NK cell infiltration without toxicity. Conclusion This study introduces three innovations: (1) a species-specific CD16A binder overcoming polymorphism limitations, (2) Fc domain engineering (N297A) to optimize stability and safety, and (3) a synergistic combination strategy with sorafenib. The results provide a translatable framework for GPC3+ solid tumor immunotherapy.

Objetive To explore the effects of hypoxia preconditioning and praeruptorin C preconditioning on phospholamban(PLB)phosphorylation in rat cardiomyocytes.Methods The neonatal rat cardiomyocytes were randomly divided into 4 groups:control group,the hypoxia preconditioning(HP)group,the praeruptorin C preconditioning(PP)group and the hypoxia-reoxygenation(HR)group.Each group was untreated or treated with protein kinase A inhibitor H-89(H-89 negative/positive group).The value of LDH of cellular supernatant was determined by automatic biochemistry analyzer.The fluorescence intensity of intracellular Ca 2+ was detected with Fluo-3/AM loading by the flow cytometer.PLB phosphorylation was measured by radioautographic technique.Results Compared with the control group,the value of LDH and the fluorescence intensity of intracellular Ca 2+ were significantly higher in HR group(P0.05),but there was no significant difference between the HP group and the control group(P0.05).Compared with control group,the value of PLB phosphorylation in HP and PP groups increased by 15.6% and by 16.8%(P0.05),while the value in HR group significantly decreased by 29.3%(P0.05).The value of phosphorylation in groups unreated with H-89 was significantly higher than that in the groups treated with H-89(P0.05).Conclusions Cardioprotection induced by hypoxia preconditioning and praeruptorin C preconditioning against hypoxia-reoxygenation injury may be related with upregulating PLB phosphorylation.