Abstract

The advancement of novel pharmaceuticals and targeted therapeutic approaches is considerably obstructed by the insufficient comprehension of the intricate pathophysiology of colorectal cancer (CRC). The therapeutic effectiveness of tyrosine kinase inhibitors (TKI)-based systemic treatment for advanced CRC is limited by medication resistance. Research has revealed that therapeutic strategies aimed at the myosin light chain kinase family member 4 (MYLK4) and its corresponding response element can suppress tumour proliferation and yield significant clinical advantages for cancer patients. This study reveals that MYLK4-mediated lipid metabolic reprogramming confers resistance to TKI-induced ferroptosis in CRC. MYLK4 directly interacts with tripartite motif containing 15 (TRIM15) in a way reliant on mouse double minute 2 homolog (MDM2), hence enhancing p53 ubiquitination and degradation. Significantly, p53 suppresses the transcription of stearoyl-CoA desaturase 1 (SCD1) through binding to its promoter. Elevated SCD1 levels correlate with increased MYLK4 levels, and their concurrent expression forecasts regorafenib resistance and poor prognosis in colorectal cancer. Regorafenib and SCD1 inhibitor (SCD1 inhibitor-3) co-treatment demonstrate promising anti-tumor efficacy in organoids and xenografted tumours derived from wild-type p53 colorectal cancer patients. Patients with colorectal cancer exhibiting elevated MYLK4 activity and wild-type p53 may derive clinical benefits from this combination therapy. These results suggest that MYLK4 may serve as a promising therapeutic target for the treatment of colorectal cancer.