Colorectal cancer (CRC) patients with fatty liver disease are significantly more likely to develop an aggressive form of liver metastasis known as the “replacement” growth pattern, researchers at KU Leuven report in a study published July 1 in Nature. The finding reveals a metabolic axis, steatosis to fatty acid oxidation to MYC activation to proline-driven collagen synthesis, that could be targeted with existing drug candidates.
The prognosis of CRC patients who develop liver metastases is heavily skewed by which of two distinct histopathological growth patterns the metastasis adopts. Patients with “replacement” metastases, where tumor cells infiltrate and replace the surrounding liver parenchyma, have a five-year overall survival rate below 44 percent, compared with 73 percent for patients with “encapsulated” (previously called desmoplastic) metastases, where the tumor is walled off by fibrous tissue. Despite this stark difference, no approved therapies specifically target replacement metastases.
The Steatosis Connection
The team, led by Sarah-Maria Fendt at the VIB-KU Leuven Center for Cancer Biology, began by examining whether liver steatosis, the accumulation of fat in liver cells, commonly known as fatty liver, might influence metastatic growth patterns. They analyzed treatment-naive CRC patients and found that those with steatosis had a significantly higher frequency of replacement metastases compared with patients whose livers were clear of fat.
Mechanistically, the researchers traced the link through a multi-step pathway. Steatosis increases fatty acid oxidation in the liver, which in turn elevates levels of acetyl-CoA. This extra acetyl-CoA drives acetylation of the MYC protein at a specific lysine residue (K323), stabilizing MYC and preventing its degradation. Stabilized MYC then activates the proline synthesis pathway by upregulating P5CS (ALDH18A1) and related enzymes PYCR1 and PYCR2. The resulting proline fuels production of collagen type I (COL1A1), a structural protein that replacement metastases depend on for growth.
The pathway is a cascade where each step creates the conditions for the next: fatty liver supplies the metabolic fuel, which activates a transcription factor, which rewires amino acid metabolism to build the scaffolding that replacement metastases need to expand.
Targeting the Axis
The researchers validated the pathway’s importance through multiple approaches. In patient-derived organoids and xenograft mouse models, pharmacological inhibition of MYC with the compound MYCi975 selectively reduced replacement metastasis growth while sparing encapsulated metastases. Knockdown of P5CS or COL1A1 similarly impaired replacement metastasis formation and growth.
Spatial metabolomics using MALDI mass spectrometry imaging confirmed that replacement metastases in patient tissue samples contained elevated proline, collagen, MYC, and P5CS levels compared to their encapsulated counterparts, evidence that the same pathway operates in human disease.
Clinical Implications
The finding is notable because both steatosis and colorectal cancer are common conditions. Nonalcoholic fatty liver disease affects an estimated 25 to 30 percent of the global adult population, driven by rising rates of obesity and metabolic syndrome. CRC is the third most commonly diagnosed cancer worldwide, and the liver is the most frequent site of distant metastasis.
The identification of MYC as a central node in this pathway is particularly relevant because MYC has been notoriously difficult to drug directly. However, the involvement of downstream enzymes like P5CS and COL1A1, which are more conventional drug targets, may offer alternative routes. The team also notes that the MYC inhibitor MYCi975 is in preclinical development, and the Phase I clinical trial of the MYC inhibitor OMO-103 (NCT04808362) has established proof of concept for targeting MYC in humans.
Caveats
The study’s primary mechanistic evidence comes from mouse models and patient-derived organoids, not from a prospective clinical trial in patients. The patient data is cross-sectional and correlational: steatosis is associated with more replacement metastases, but direct causality in humans has not been proven. The MYCi975 data is from mice; whether the compound will show similar selectivity in human patients remains to be tested.
Additionally, the study looked only at CRC liver metastases. Whether the same steatosis-metastasis axis operates in other cancers that spread to the liver, such as pancreatic, breast, or lung cancer, is an open question.
Disclosure: Based on a peer-reviewed paper in Nature, published July 1, 2026. DOI: 10.1038/s41586-026-10686-2. Senior author S.-M. Fendt reports funding from BlackBelt Therapeutics, Auron Therapeutics, and Alesta Therapeutics, and advisory roles with Alesta, Fund+, and Droia Ventures.