Background. PANoptosis has been a research hotspot, but the role of PANoptosis in hepatocellular carcinoma (HCC) remains widely unknown. Drug resistance and low response rate are the main limitations of chemotherapy and immunotherapy in HCC. Thus, construction of a prognostic signature to predict prognosis and recognize ideal patients for corresponding chemotherapy and immunotherapy is necessary. Method. The mRNA expression data of HCC patients was collected from TCGA database. Through LASSO and Cox regression, we developed a prognostic signature based on PANoptosis-related genes. KM analysis and ROC curve were implemented to evaluate the prognostic efficacy of this signature, and ICGC and GEO database were used as external validation cohorts. The immune cell infiltration, immune status, and IC50 of chemotherapeutic drugs were compared among different risk subgroups. The relationships between the signature and the efficacy of ICI therapy, sorafenib treatment, and transcatheter arterial chemoembolization (TACE) therapy were investigated. Result. A 3-gene prognostic signature was constructed which divided the patients into low- and high-risk subgroups. Low-risk patients had better prognosis, and the risk score was proved to be an independent predictor of overall survival (OS), which had a well predictive effect. Patients in high-risk population had more immunosuppressive cells (Tregs, M0 macrophages, and MDSCs), higher TIDE score and TP53 mutation rate, and elevated activity of base excision repair (BER) pathways. Patients with low risk benefited more from ICI, TACE, and sorafenib therapy. The predictive value of the risk score was comparable with TIDE and MSI for OS under ICI therapy. The risk score could be a biomarker to predict the response to ICI, TACE, and sorafenib therapy. Conclusion. The novel signature based on PANoptosis is a promising biomarker to distinguish the prognosis predict the benefit of ICI, TACE, and sorafenib therapy, and forecast the response to them.

We have previously demonstrated that the PI3K/Akt/mTOR signaling pathway was closely linked to the lipid metabolism homeostasis in goose primary hepatocytes. Recently, it was demonstrated that endoplasmic reticulum stress (ERS) can not only affect lipogenesis, but also is related to the PI3K/Akt/mTOR signaling pathway, so it was hypothesised that ERS can affect the lipid metabolism through the PI3K/Akt/mTOR signaling pathway. The ERS model was established by treating goose primary hepatocytes with tunicamycin (TM), and then incubated with PI3K/Akt/mTOR signaling pathway inhibitors LY294002 (LY), Rapamycin (Ra) or NVP-BEZ235 (NVP). Hepatocytes were assigned into 5 groups, including control group, TM group, TM+LY group, TM+Ra group, and TM+NVP group. The results showed that compared with the control group, the mRNA expression and the protein content of BIP/GRP78 significantly increased (P< 0.05) in the TM group, indicating that the ERS model was established successfully. The result of Oil Red O staining revealed that TM caused an increase (P< 0.05) in lipid accumulation and in the mRNA expression of PI3K and S6K, implying that ERS could activate the PI3K/Akt/mTOR signaling pathway.Compared with the TM group, the mRNA expression of genes involved in the PI3K/Akt/mTOR signaling pathway (PI3K, Akt1, mTOR and S6K), lipogenesis (ACCα, FAS and SREBP-1), VLDL-TG assembly and secretion (MTTP, DGAT1 and DGAT2) significantly decreased (P< 0.05) in the TM+LY group, the TM+Ra group, and the TM+NVP group, whereas the protein content of CPT1 and MTTP significantly increased (P< 0.05) in the TM+LY group, the TM+Ra group, and the TM+NVP group. These findings suggest that inhibition of the PI3K/Akt/mTOR signaling pathway can effectively decrease the steatosis mediated by ERS in goose hepatocytes.