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Abstract FAM210B (family with sequence similarity 210 member B) is a novel protein that has been linked to tumor development. However, its role and underlying mechanisms in lung adenocarcinoma (LUAD) progression remain largely unexplored. In this study, FAM210B was observed to be down-regulated in LUAD cells. Analyses of public datasets revealed that decreased expression of FAM210B predicts poor survival. Accordingly, in vitro and in vivo studies have confirmed the inhibitory role of FAM210B on the growth and tumor metastasis of LUAD cells. RNA-seq analysis further indicated that FAM210B plays a role in regulating innate immune-related signaling pathways in LUAD cells, particularly involving the production of type I interferon (IFN-α/β). Specifically, FAM210B activates STAT1/IRF9/IFIT3 axis by upregulating IFN-α/β expression, leading to the inhibition of proliferation and migration of LUAD cells. Furthermore, TOM70 (Translocase of outer mitochondrial membrane 70, also named as TOMM70) has been identified as a functional interacting partner of FAM210B in its modulation on the expression of IFN-α/β, as well as the proliferative and metastatic phenotypes of LUAD cells. In conclusion, our study indicates that FAM210B is an important suppressor of cellular viability and mobility during lung cancer progression.

Kidney fibrosis is associated with tubular injury, oxidative stress and activation of interstitial fibroblasts. However, whether these events are somehow connected is poorly understood. In this study, we show that glutathione peroxidase-3 (GPX3) depletion in renal tubular epithelium after kidney injury plays a central role in orchestrating an oxidatively stressed extracellular microenvironment, which drives interstitial fibroblast activation and proliferation. Through transcriptional profiling by RNA-sequencing, we found that the expression of GPX3 was down-regulated in various models of chronic kidney disease (CKD), which was correlated with induction of nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase-4 (NOX4). By using decellularized extracellular matrix (ECM) scaffold, we demonstrated that GPX3-depleted extracellular microenvironment spontaneously induced NOX4 expression and reactive oxygen species (ROS) production in renal fibroblasts and triggered their activation and proliferation. Activation of NOX4 by advanced oxidation protein products (AOPPs) mimicked the loss of GPX3, increased the production of ROS, stimulated fibroblast activation and proliferation, and activated protein kinase C-α (PKCα)/mitogen-activated protein kinase (MAPK)/signal transducer and activator of transcription 3 (STAT3) signaling. Silencing NOX4 or inhibition of MAPK with small molecule inhibitors hampered fibroblast activation and proliferation. In mouse model of CKD, knockdown of NOX4 repressed renal fibroblast activation and proliferation and alleviated kidney fibrosis. These results indicate that loss of GPX3 orchestrates an oxidatively stressed extracellular microenvironment, which promotes fibroblast activation and proliferation through a cascade of signal transduction. Our studies underscore the crucial role of extracellular microenvironment in driving fibroblast activation and kidney fibrosis.

Klotho is an anti-ageing protein whose expression is downregulated in chronic kidney disease, but the large size of the protein makes it challenging to deliver therapeutically. Here, the authors develop a Klotho-derived peptide, and show that it recapitulates the anti-fibrotic action of Klotho and prevents kidney fibrosis in mice by targeting TGF-β signalling.

BackgroundThis study aimed to identify biological markers for diabetic nephropathy (DN) and explore their underlying mechanisms.MethodsFour datasets, GSE30528, GSE47183, GSE104948, and GSE96804, were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified using the “limma” package, and the “RobustRankAggreg” package was used to screen the overlapping DEGs. The hub genes were identified using cytoHubba of Cytoscape. Logistic regression analysis was used to further analyse the hub genes, followed by receiver operating characteristic (ROC) curve analysis to predict the diagnostic effectiveness of the hub genes. Correlation analysis and enrichment analysis of the hub genes were performed to identify the potential functions of the hub genes involved in DN.ResultsIn total, 55 DEGs, including 38 upregulated and 17 downregulated genes, were identified from the three datasets. Four hub genes (FN1, CD44, C1QB, and C1QA) were screened out by the “UpSetR” package, and FN1 was identified as a key gene for DN by logistic regression analysis. Correlation analysis and enrichment analysis showed that FN1 was positively correlated with four genes (COL6A3, COL1A2, THBS2, and CD44) and with the development of DN through the extracellular matrix (ECM)–receptor interaction pathway.ConclusionsWe identified four candidate genes: FN1, C1QA, C1QB, and CD44. On further investigating the biological functions of FN1, we showed that FN1 was positively correlated with THBS2, COL1A2, COL6A3, and CD44 and involved in the development of DN through the ECM–receptor interaction pathway. THBS2, COL1A2, COL6A3, and CD44 may be novel biomarkers and target therapeutic candidates for DN.