Mutant p53 leads to low-grade IFN-I-induced inflammation and impairs cGAS-STING signalling in mice.

Type I interferons (IFN-Is) are a class of proinflammatory cytokines produced in response to viruses and environmental stimulations, resulting in chronic inflammation and even carcinogenesis. However, the connection between IFN-I and p53 mutation is poorly understood. Here, we investigated IFN-I status in the context of mutant p53 (p53N236S , p53S). We observed significant cytosolic double-stranded DNA (dsDNA) derived from nuclear heterochromatin in p53S cells, along with an increased expression of IFN-stimulated genes. Further study revealed that p53S promoted cyclic GMP-AMP synthase (cGAS) and IFN-regulatory factor 9 (IRF9) expression, thus activating the IFN-I pathway. However, p53S/S mice were more susceptible to herpes simplex virus 1 infection, and the cGAS-stimulator of IFN genes (STING) pathway showed a decline trend in p53S cells in response to poly(dA:dT) accompanied with decreased IFN-ß and IFN-stimulated genes, whereas the IRF9 increased in response to IFN-ß stimulation. Our results illustrated the p53S mutation leads to low-grade IFN-I-induced inflammation via consistent low activation of the cGAS-STING-IFN-I axis, and STAT1-IRF9 pathway, therefore, impairs the protective cGAS-STING signalling and IFN-I response encountered with exogenous DNA attack. These results suggested the dual molecular mechanisms of p53S mutation in inflammation regulation. Our results could be helping in further understanding of mutant p53 function in chronic inflammation and provide information for developing new therapeutic strategies for chronic inflammatory diseases or cancer.

Single-cell and bulk RNA-sequencing analysis to predict the role and clinical value of CD36 in lung squamous cell carcinoma.

The majority of patients with lung squamous cell carcinoma are diagnosed at an advanced stage, which poses a challenge to the efficacy of chemotherapy. Therefore, the search for an early biomarker needs to be addressed. CD36 is a scavenger receptor expressed in various cell types. It has been reported that it is closely related to the occurrence and development of many kinds of tumours. However, its role in lung squamous cell carcinoma has not been reported. Our research aims to reveal the role of CD36 in lung squamous cell carcinoma by integrating single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing data. We used bioinformatics methods to explore the potential carcinogenicity of CD36 by analysing the data from the cancer genome map (TCGA), gene expression comprehensive map (GEO), human protein map (HPA) comparative toxicology genomics database (CTD) and other resources. Our study dissected the relationship between CD36 and prognosis and gene correlation, functional analysis, mutation of different tumours, infiltration of immune cells and exploring the interaction between CD36 and chemicals. The results showed that the expression of CD36 was heterogeneous. Compared with normal patients, the expression was low in lung squamous cell carcinoma. In addition, CD36 showed early diagnostic value in four kinds of tumours (LUSC, BLCA, BRCA and KIRC) and was positively or negatively correlated with the prognosis of different tumours. The relationship between CD36 and the tumour immune microenvironment was revealed by immunoinfiltration analysis, and many drugs that might target CD36 were identified by the comparative toxicological genomics database (CTD). In summary, through pancancer analysis, we found and verified for the first time that CD36 may play a role in the detection of lung squamous cell carcinoma. In addition, it has high specificity and sensitivity in detecting cancer. Therefore, CD36 can be used as an auxiliary index for early tumour diagnosis and a prognostic marker for lung squamous cell carcinoma.