Tissue-resolved molecular landscape reveals hepatic regulatory networks and metabolic mediators underlying feed efficiency in chickens

INTRODUCTION: Residual feed intake (RFI) is a key indicator of feed efficiency in poultry and is regulated by coordinated physiological processes across multiple tissues. Improving feed efficiency is essential for sustainable poultry production; however, its genetic and molecular basis, particularly the relationship between feed efficiency and fat deposition during the extended laying period, remains incompletely understood. OBJECTIVES: This study aimed to identify the molecular features underlying feed efficiency and to elucidate its molecular relationship with fat deposition during the extended laying period in laying hens. METHODS: Whole-genome resequencing was integrated with multi-tissue transcriptomic and metabolomic profiling of 248 laying hens. Genetic association analyses, multi-tissue cis-eQTL mapping, cross-omics integration analyses, and molecular subtyping were combined with machine learning and hepatocyte-based functional assays to prioritize and evaluate candidate genes and metabolites associated with RFI at 100 weeks of age (100wRFI). RESULTS: Genetic analyses highlighted a genomic locus associated with 100wRFI. Integrative multi-omics analyses prioritized putative causal genes and metabolites across tissues, among which PCCB emerged as a recurrent multi-tissue candidate forming a liver-centered gene-metabolite-phenotype axis with PE(18:0/20:4(8Z,11Z,14Z,17Z)). Functional perturbation of PCCB in hepatocytes was associated with altered hepatic lipogenesis, redox status, mitochondrial membrane potential, and inflammatory signaling. Multi-tissue molecular features associated with 100wRFI showed stable predictive performance for fat deposition-related traits, and lysophosphatidylinositol LPI(18:1) was identified as a putative metabolic mediator promoting hepatic lipid accumulation in vitro. CONCLUSIONS: This study delineates the tissue-resolved molecular landscape of feed efficiency in hens during the extended laying period and highlights hepatic regulatory networks linking lipid metabolism, cellular homeostasis, and feed efficiency. These findings underscore the close molecular coupling between feed efficiency and fat deposition and provide a resource and framework for future functional studies and strategies to improve feed efficiency.