Kliesow Remes, A. | bioRxiv Science

bioRxiv2026

Multi-Lab Testing of Early Preclinical Discoveries Identifies Promising Treatments

A fundamental challenge in drug development is the frequent failure of early laboratory research to translate into clinical benefit. One promising solution is to confirm findings from exploratory single-laboratory studies across multiple laboratories before clinical testing. We investigated this approach following the conduct of preclinical multi-laboratory studies across different fields of medicine. For this, we evaluated effect sizes, experimental rigor, and a set of criteria to identify determinants of confirmation success. When tested under increased rigor, only a fraction of multi-laboratory studies confirmed the initial results. The underlying effect size reduction was associated with outcome-relevant experimental differences between exploratory and confirmatory stages. In summary, multi-laboratory studies proved highly informative and served as an effective filter for promising treatments.

scientific communication and education↗

bioRxiv2026

FYCO1 improves postischemic cardiac remodeling via enhanced autophagic flux and attenuation of proinflammatory signaling

Acute myocardial infarction (MI) is associated with severe metabolic and oxidative stress that triggers cardiomyocyte death, pro-inflammatory signaling and progressive structural remodeling frequently culminating in heart failure. Although significant advances in reperfusion therapy improved acute survival in patients, therapeutic strategies that directly target intracellular processes in response to injury remain limited. One key response mechanism, autophagy, is rapidly activated to ameliorate ischemic stress. Yet, defective autophagic flux may exacerbate cardiomyocyte injury and maladaptive tissue remodeling. Here we identify FYCO1 as a cardiomyocyte-enriched key regulator of autophagy that enhances autophagic flux and promotes myocardial resilience following ischemic injury. Using cardiomyocyte-specific FYCO1 transgenic mice subjected to permanent coronary ligation, we demonstrate that FYCO1 overexpression limits infarct expansion, reduces cardiomyocyte injury, and preserves cardiac function during remodeling. In vivo RFP-EGFP-LC3 autophagy reporter analyses reveal that FYCO1 promotes a sustained increase of autophagic flux by coordinating autophagosome formation and efficient autolysosomal clearance. Transcriptomic profiling identifies a cardioprotective gene program in FYCO1-Tg animals subjected to MI, with suppression of proinflammatory, proapoptotic and stress-response pathways. Systemic serum cytokine and chemokine profiling as well as transcriptomic analyses of myocardium confirm reduced inflammatory signaling and subsequent reduction in macrophage recruitment into the infarct border zone. Together these findings position FYCO1 as a key regulator of cardiomyocyte autophagy and reveal a previously unrecognized link between autophagy and inflammation in shaping cardiac remodeling following myocardial infarction. FYCO1-mediated autophagy promotes myocardial preservation and functional recovery, highlighting autophagic flux as a promising target for cardioprotective interventions.

molecular biology↗