Cardiovascular disease(CVD)is a leading cause of death worldwide,posing a substantial burden on so-ciety.Transfer RNA-derived fragment(tRF)is a novel class of non-coding small RNA produced primarily through the specific cleavage of precursor or mature transfer RNA(tRNA).Unlike the canonical role of tRNA in amino acid trans-port,tRF plays important roles in regulating gene transcription,translation,and epigenetic modifications,thereby influen-cing pathophysiological processes such as cell proliferation,differentiation,and apoptosis.In recent years,with the wide-spread application of small RNA sequencing technologies,a growing number of studies have demonstrated close associations between tRF and the development and progression of various CVDs,making them a research hotspot in the field.This re-view systematically summarizes the origin,classification,functional mechanisms,and recent advances in tRF research re-lated to CVD,aiming to provide new directions for understanding the pathogenesis of CVD and identifying potential thera-peutic targets.

Cardiovascular disease(CVD)is a leading cause of death worldwide,posing a substantial burden on so-ciety.Transfer RNA-derived fragment(tRF)is a novel class of non-coding small RNA produced primarily through the specific cleavage of precursor or mature transfer RNA(tRNA).Unlike the canonical role of tRNA in amino acid trans-port,tRF plays important roles in regulating gene transcription,translation,and epigenetic modifications,thereby influen-cing pathophysiological processes such as cell proliferation,differentiation,and apoptosis.In recent years,with the wide-spread application of small RNA sequencing technologies,a growing number of studies have demonstrated close associations between tRF and the development and progression of various CVDs,making them a research hotspot in the field.This re-view systematically summarizes the origin,classification,functional mechanisms,and recent advances in tRF research re-lated to CVD,aiming to provide new directions for understanding the pathogenesis of CVD and identifying potential thera-peutic targets.

The efficient clinical treatment of oral squamous cell carcinoma(OSCC)is still a challenge that demands the development of effective new drugs.Phenformin has been shown to produce more potent anti-tumor activities than metformin on different tumors,however,not much is known about the influence of phenformin on OSCC cells.We found that phenformin suppresses OSCC cell proliferation,and promotes OSCC cell autophagy and apoptosis to significantly inhibit OSCC cell growth both in vivo and in vitro.RNA-seq analysis revealed that autophagy pathways were the main targets of phenformin and identified two new targets DDIT4(DNA damage inducible transcript 4)and NIBAN1(niban apoptosis regulator 1).We found that phenformin significantly induces the expression of both DDIT4 and NIBAN1 to promote OSCC autophagy.Further,the enhanced expression of DDIT4 and NIBAN1 elicited by phenformin was not blocked by the knockdown of AMPK but was suppressed by the knockdown of transcription factor ATF4(activation transcription factor 4),which was induced by phenformin treatment in OSCC cells.Mechanistically,these results revealed that phenformin triggers endoplasmic reticulum(ER)stress to activate PERK(protein kinase R-like ER kinase),which phosphorylates the transitional initial factor eIF2,and the increased phosphorylation of eIF2 leads to the increased translation of ATF4.In summary,we discovered that phenformin induces its new targets DDIT4 and especially NIBAN1 to promote autophagic and apoptotic cell death to suppress OSCC cell growth.Our study supports the potential clinical utility of phenformin for OSCC treatment in the future.