Serine/arginine-rich splicing factors (SRSFs) refer to twelve RNA-binding proteins which regulate splice site recognition and spliceosome assembly during precursor messenger RNA splicing. SRSFs also participate in other RNA metabolic events, such as transcription, translation and nonsense-mediated decay, during their shuttling between nucleus and cytoplasm, making them indispensable for genome diversity and cellular activity. Of note, aberrant SRSF expression and/or mutations elicit fallacies in gene splicing, leading to the generation of pathogenic gene and protein isoforms, which highlights the therapeutic potential of targeting SRSF to treat diseases. In this review, we updated current understanding of SRSF structures and functions in RNA metabolism. Next, we analyzed SRSF-induced aberrant gene expression and their pathogenic outcomes in cancers and non-tumor diseases. The development of some well-characterized SRSF inhibitors was discussed in detail. We hope this review will contribute to future studies of SRSF functions and drug development targeting SRSFs.

Lung cancer is one of the most aggressive cancers with poor prognosis and high resistance rate. The family of signal transducer and activator of transcriptions (STATs) appears to modulate resistance in non-small cell lung cancer (NSCLC). In this work, we demonstrated that STAT3/ZEB1 is a critical axis in gefitinib resistance. STAT3-targeted inhibition therefore is a new potential therapeutic strategy for gefitinib resistance in lung cancer. Our small molecule screening identified a relatively specific STAT3-targeted inhibitor, LL1. Pharmacological and biochemical studies indicated that LL1 block the activation of STAT3 via inhibiting its phosphorylation. Further in vitro and in vivo studies elucidated that LL1 sensitizes the resistance cells to gefitinib through depleting STAT3 activity and blocking STAT3/ZEB1 signaling pathways. Little toxicity of LL1 was observed in animal models. All these favorable results indicated that LL1 is a chemotherapeutic adjuvant for gefitinib resistance in NSCLC.

Silencing STAT3 is confirmed as a promising therapeutic strategy for triple-negative breast cancer (TNBC) therapy to address the issue of its poor prognosis. In this study, the natural product cryptotanshinone was firstly remodeled and modified as a more effective STAT3 inhibitor by structure-based strategy. The synthetic derivative KYZ3 had 22–24-fold increase in antitumor activity than cryptotanshinone on two TNBC cell lines but had little effect on normal breast epithelial MCF-10A cells. Further investigation showed that KYZ3 inhibited persistent STAT3 phosphorylation. It also prevented the STAT3 protein nuclear translocation to regulate the expressions of the target oncogenes including Bax and Bcl-2. Furthermore, KYZ3 inhibited TNBC cell metastasis by decreasing the levels of MMP-9 which were directly regulated by activated STAT3. A STAT3 plasmid transfecting assay suggested that KYZ3 induced tumor cell apoptosis mainly by targeting STAT3. Finally, KYZ3 suppressed the growth of tumors resulting from subcutaneous implantation of MDA-MB-231 cells in vivo. Taken together, KYZ3 may be a promising cancer therapeutic agent for TNBC.