Cholesterol synthases suppress metastasis and stemness through PDIA4/ACLY or SYVN1/SCD1 axis in advanced colorectal cancer.

Aberrant cholesterol biosynthesis is a notable hallmark of cancers, supporting unlimited cell proliferation. Previously, we delineated that cholesterol synthases FDFT1 and SQLE promoted colorectal cancer (CRC) cell proliferation, while how these enzymes influence CRC metastasis and stemness remains unclear. This study demonstrates that suppress of FDFT1 or SQLE enhances CRC metastasis and stemness through impairing ER stress and degrading PDIA4 or SYVN1 individually. Additionally, the function of FDFT1 and SQLE on CRC metastasis relies on tryptophan. Tryptophan augments PDIA4-ACLY and SYVN1-SCD1 co-complex association to drive CRC metastasis and stemness. Consequently, the specific inhibitor of ACLY or SCD1 blocks FDFT1 or SQLE deficiency induced CRC metastasis using Male BALB/c nude mice. Besides, sub-cytotoxic concentrations of inhibitors targeting FDFT1 or SQLE generate the invasive feature in CRC cells. Overall, these findings indicate that cholesterol synthases impact ER homeostasis and fatty acid synthesis to regulate CRC metastasis and stemness, offering potential for combined targeted therapies in CRC.