Hnrnpd, also known as AUF1, is a heterogeneous nuclear ribonucleoprotein family member with both cytoplasmic and nuclear roles. It is an RNA-binding protein involved in post-transcriptional regulation, which can affect processes such as RNA splicing, nuclear export, stability, and translation [2,4]. Hnrnpd participates in multiple cellular physiological processes, including the cell cycle and apoptosis, and is associated with various diseases like cancer and neurodegenerative diseases [1,2].

In terms of circRNA biogenesis, depletion of Hnrnpd in cells primarily increases the levels of exonic circular RNAs (ecircRNAs). Hnrnpd preferentially binds to A-and U-rich motifs, and the flanking introns of ecircRNAs have more of its binding sites. For a small set of genes, the circRNA:mRNA ratio is affected, such as in the case of CDK1 where Hnrnpd suppresses circCDK1 biogenesis and favors CDK1 mRNA generation, and CDK1 protein is a key regulator of the cell cycle and apoptosis [1]. In Parkinson's disease-related studies, AUF1/Hnrnpd binds to the 3'UTR of SNCA transcripts, regulating their nuclear export, stability, and translation [2]. In lung adenocarcinoma, high levels of Hnrnpd and MAD2L2 proteins are found, and Hnrnpd binds to the MAD2L2 promoter, forming a regulatory axis. Down-regulation of the Hnrnpd/MAD2L2 axis inhibits lung adenocarcinoma progression by suppressing the PI3K/HIF1α/ANGPTL4 pathway and tumor angiogenesis [3].

In conclusion, Hnrnpd is a crucial RNA-binding protein involved in multiple post-transcriptional regulatory processes. Gene knockout-based research, as in the studies mentioned, has revealed its roles in various biological processes and disease conditions such as cell cycle regulation, apoptosis, and cancer progression. Understanding Hnrnpd functions provides insights into the molecular mechanisms underlying these biological phenomena and disease development, potentially offering new therapeutic targets for related diseases.