Intracellular lipid droplets positively regulate the dormancy of colorectal cancer cells depending on ELF1-ACSL5 signaling

BACKGROUND: Colorectal cancer recurrence is largely attributed to dormant tumor cells that evade therapy. The role of organelle metabolism, particularly lipid droplets (LDs) accumulation, in maintaining tumor dormancy remains poorly understood. This study aimed to investigate how LDs contribute to dormancy and to identify key regulatory mechanisms. METHODS: Using patient-derived xenograft models and colorectal cancer cell lines, we established chemotherapy-induced dormant, proliferative, and recurrent cells. Transcriptomic profiling identified key regulatory genes and lipidomics of LDs was performed by Liquid Chromatography‑Tandem Mass Spectrometry. Functional validation was performed via genetic knockdown/overexpression, pharmacological inhibition, and mutational analysis. Lipid droplet content, reactive oxygen species levels, and dormancy markers were assessed using staining, flow cytometry, and immunoblotting. Clinical correlation was evaluated using patient datasets and survival analysis. RESULTS: Dormant cells exhibited elevated LD levels compared to proliferative or recurrent cells. Transcriptomic analysis identified ACSL5 as a key upregulated gene in dormant cells. ACSL5 promoted LD accumulation, which in turn reduced intracellular reactive oxygen species and stabilized dormancy by sequestering oxidized lipids. The transcription factor ELF1 directly bound the ACSL5 promoter, establishing the ELF1-ACSL5 regulatory axis. Disruption of this axis depleted LDs, increased ROS, and forced dormant cells to exit dormancy. Clinically, high ACSL5 expression correlated with poor prognosis in colorectal cancer patients. CONCLUSION: This study defines a novel ELF1-ACSL5-lipid droplet axis that maintains colorectal cancer dormancy by promoting lipid sequestration and redox homeostasis. These findings reveal organelle-centric metabolic reprogramming as a fundamental dormancy mechanism and nominate this axis as a promising therapeutic target to prevent cancer recurrence.