Lan Qun, Liufu Sui, Xu Xin, Chen Bohe, Chen Wenwu, Wang Kaiming, Liu Caihong, Xiao Lanlin, Liu Xiaolin, Yi Lei, Liu Jingwen, Deng Qiuchun, Ma Haiming, Kang Meng
Hunan Agricultural University & Yuelushan Laboratory & Key Laboratory of Livestock and Poultry Resources Evaluation and Utilization, Ministry of Agriculture and Rural Affairs, Changsha, 410128, China.
BMC Genomics. 2025 Aug 5;26(1):724. doi: 10.1186/s12864-025-11896-0.
Growth retardation is a globally prevalent clinical issue, particularly in preterm offspring. It frequently occurs during the early postnatal development of piglets and results in high mortality. In addition to slow postnatal growth caused by complications from immature organs, these offspring are also at risk of facing significant long-term health challenges in adulthood. The liver plays a crucial role in regulating nutrient metabolism and immune function and frequently communicates with other organs to maintain overall health. However, the multifaceted mechanisms by which the liver regulates growth retardation in offspring remain largely unexplored.
Here, we selected piglets exhibiting extreme weight variations at both birth and weaning stages for comprehensive histomorphological and multi-omics analysis in the liver. Compared to high weaning weight (HWW) piglets, the liver of low weaning weight (LWW) piglets was predominantly characterized by hepatic vacuolation and structural lesions. Transcriptomic analysis of the liver indicated that differentially expressed genes (DEGs) linked to amino acid metabolism (, , and ) and innate immune (, , and ) showed significant upregulation in the high birth weight (HBW) piglets when compared to the low birth weight (LBW) piglets. Furthermore, DEGs identified at the weaning stage are primarily enriched in PPAR signaling pathway, protein digestion and absorption, glutathione metabolism, tryptophan metabolism, and ferroptosis. Notably, ferroptosis was the only pathway that showed overlapping enrichment in the KEGG enrichment analysis across all three omics datasets. Gene and significantly differential metabolites (SDMs) (L-glutathione, L-cysteine, and Gamma-glutamylcysteine) were co-enriched in ferroptosis and showed higher levels in HWW piglets. The elevation of these genes and metabolites plays a key role in scavenging reactive oxygen species (ROS) accumulation and suppressing hepatic ferroptosis. Notably, was positively associated with L-glutathione and Gamma-glutamylcysteine, and these two metabolites were positively correlated with weaning weight, implying a potential role of these metabolites in improving growth performance. Finally, integrative analysis of RNA-seq and ATAC-seq data revealed several differentially accessible regions (DARs), which were annotated to the genes , , , , and . The transcription factor (TF)-gene regulatory network revealed that five DEGs (, , , , and ) are the downstream target genes of TFs, including and . These target DEGs are involved in liver development and the pathogenesis of hepatic disease.
Taken together, the genes and metabolites identified in this study provide gene-targeted and nutrition-based therapeutic strategies for piglets with growth limitations during the lactation and even post-weaning stages. Our findings also provide epigenetic insights into the molecular mechanisms underlying liver-mediated modulation of growth and development in offspring.
The online version contains supplementary material available at 10.1186/s12864-025-11896-0.
生长发育迟缓是一个全球普遍存在的临床问题，在早产后代中尤为明显。它经常发生在仔猪出生后的早期发育阶段，并导致高死亡率。除了因器官不成熟引发的并发症导致出生后生长缓慢外，这些后代在成年后还面临着重大的长期健康挑战风险。肝脏在调节营养代谢和免疫功能方面起着关键作用，并经常与其他器官相互作用以维持整体健康。然而，肝脏调节后代生长发育迟缓的多方面机制在很大程度上仍未被探索。
在这里，我们选择了在出生和断奶阶段体重差异极大的仔猪，对其肝脏进行全面的组织形态学和多组学分析。与高断奶体重（HWW）仔猪相比，低断奶体重（LWW）仔猪的肝脏主要特征为肝空泡化和结构损伤。肝脏的转录组分析表明，与氨基酸代谢（、和）和先天免疫（、和）相关的差异表达基因（DEGs）在高出生体重（HBW）仔猪中与低出生体重（LBW）仔猪相比显著上调。此外，在断奶阶段鉴定出的DEGs主要富集在PPAR信号通路、蛋白质消化与吸收、谷胱甘肽代谢、色氨酸代谢和铁死亡中。值得注意的是，铁死亡是在所有三个组学数据集中的KEGG富集分析中唯一显示重叠富集的通路。基因和显著差异代谢物（SDMs）（L-谷胱甘肽、L-半胱氨酸和γ-谷氨酰半胱氨酸）在铁死亡中共同富集，并且在HWW仔猪中水平更高。这些基因和代谢物的升高在清除活性氧（ROS）积累和抑制肝脏铁死亡中起关键作用。值得注意的是，与L-谷胱甘肽和γ-谷氨酰半胱氨酸呈正相关，并且这两种代谢物与断奶体重呈正相关，这意味着这些代谢物在改善生长性能方面具有潜在作用。最后，RNA-seq和ATAC-seq数据的综合分析揭示了几个差异可及区域（DARs），这些区域被注释到基因、、、和。转录因子（TF）-基因调控网络显示，五个DEGs（、、、和）是TFs的下游靶基因，包括和。这些靶DEGs参与肝脏发育和肝脏疾病的发病机制。
综上所述，本研究中鉴定出的基因和代谢物为哺乳期甚至断奶后阶段生长受限的仔猪提供了基于基因靶向和营养的治疗策略。我们的研究结果还为肝脏介导的后代生长发育调节的分子机制提供了表观遗传学见解。
在线版本包含可在10.1186/s12864-025-11896-0获取的补充材料。
