Microcolin H, a novel autophagy inducer, exerts potent antitumour activity by targeting PITPα/β

The identification of effective drug targets and the development of bioactive molecules are areas of high need in cancer therapy.The phosphatidylinositol transfer protein alpha/beta isoform(PITPα/β)has been reported to play an essential role in integrating phosphoinositide trafficking and lipid metabolism in diverse cellular processes but remains unexplored as a potential target for cancer treatment.Herein,data analysis of clinical cancer samples revealed that PITPα/βexpression is closely correlated with the poor prognosis.Target identification by chemical proteomic methods revealed that microcolin H,a naturally occurring marine lipopeptide,directly binds PITPα/βand displays antiproliferative activity on different types of tumour cell lines.Furthermore,we identified that microcolin H treatment increased the conversion of LC3I to LC3II,accompanied by a reduction of the level of p62 in cancer cells,leading to autophagic cell death.Moreover,microcolin H showed preeminent antitumour efficacy in nude mouse subcutaneous tumour models with low toxicity.Our discoveries revealed that by targeting PITPα/β,microcolin H induced autophagic cell death in tumours with efficient anti-proliferating activity,which sheds light on PITPα/βas a promising therapeutic target for cancer treatment.