The fibroblast hormone Endotrophin is a biomarker of mortality in chronic diseases

•Endotrophin is a signaling molecule derived by the post-translational modification of type VI collagen upon collagen formation.•Circulating levels of endotrophin, measured by the PRO-C6 assay, have been associated to an increased risk of mortality in several chronic diseases.•In this meta-analysis, the association of circulating endotrophin with risk of mortality has been assessed in more than 15,000 patients with a plethora of chronic diseases. A doubling in circulating endotrophin presented a hazard ratio for 3-year mortality of 2.1 when adjusted for age, sex and BMI.•Since endotrophin is a product of fibroblast activation, and it has been associated to pro-fibrotic and pro-inflammatory effects in numerous in vitro and in vivo studies, the data suggest that this molecule can be used as a biomarker reflecting an excessive fibroblast activation, which is implicated in the processes of “wound that does not heal” ultimately leading to fibrosis.•Endotrophin is a potential new marker to be employed to risk stratify patients and identify an endotype of patients with overactivation of fibroblasts, which will benefit from anti-fibrotic treatments. Fibrosis, driven by fibroblast activities, is an important contributor to morbidity and mortality in most chronic diseases. Endotrophin, a signaling molecule derived from processing of type VI collagen by highly activated fibroblasts, is involved in fibrotic tissue remodeling. Circulating levels of endotrophin have been associated with an increased risk of mortality in multiple chronic diseases. We conducted a systematic literature review collecting evidence from original papers published between 2012 and January 2023 that reported associations between circulating endotrophin (PROC6) and mortality. Cohorts with data available to the study authors were included in an Individual Patient Data (IPD) meta-analysis that evaluated the association of PROC6 with mortality (PROSPERO registration number: CRD42023340215) after adjustment for age, sex and BMI, where available. In the IPD meta-analysis including sixteen cohorts of patients with different non-communicable chronic diseases (NCCDs) (N = 15,205) the estimated summary hazard ratio for 3-years all-cause mortality was 2.10 (95 % CI 1.75—2.52) for a 2-fold increase in PROC6, with some heterogeneity observed between the studies (I2=70 %). This meta-analysis is the first study documenting that fibroblast activities, as quantified by circulating endotrophin, are independently