| Sumario: | Simple Summary: Many patients with advanced cancer lose weight and muscle, even if some eat well. This condition, called cancer cachexia, causes a reduced quality of life, increases the side effects of cancer treatment, and shortens life. Cachexia is often linked to systemic inflammation. To better treat this condition, it is essential to understand more about its biological background. We studied small molecules in the blood called microRNAs, which help to control the way genes work. We compared patients depending on whether they had cachexia and/or systemic inflammation. Patients with both cachexia and inflammation had a different microRNA profile and lived for a shorter time. These findings support that inflammation plays an important role in cachexia and should be a part of how we diagnose it. The study also shows that microRNAs in the blood might help doctors detect cachexia earlier and understand how it affects the body. Cancer cachexia is a complex syndrome marked by involuntary weight and muscle loss, often driven by systemic inflammation. This multicenter, longitudinal observational study investigated circulating microRNA (miRNA) profiles in patients with unresectable locally advanced or metastatic colorectal cancer, comparing those with and without cachexia and inflammation. A total of 168 patients were categorized into four groups based on cachexia and C-reactive protein (CRP) levels. Cachexia was defined using the 2011 consensus criteria, incorporating weight loss, low BMI, and sarcopenia. Patients with both cachexia and systemic inflammation exhibited significantly distinct miRNA profiles as well as poorer overall survival (HR 2.10, p < 0.001) compared to patients with neither condition. No significant differences were observed in patients lacking either cachexia or inflammation or both. Inflammatory cachexia emerged as a biologically distinct entity, with 82 differentially expressed miRNAs. The miR-320-family, miR-6087, miR-4488, miR-29a-3p, miR-194-5p, and miR-10a-5p were most altered, several of which are linked to muscle mass, metabolism, lipid, and protein synthesis. These findings highlight the pivotal role of systemic inflammation in cancer cachexia and support its inclusion in diagnostic criteria. Moreover, circulating miRNAs may serve as promising biomarkers for identifying cachexia in cancer patients.
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