Background <p>The Chinese mitten crab (<i>Eriocheir sinensis</i>) is a commercially important crustacean, highly valued in China and Korean peninsula for its nutritional benefits and delicate flavor. However, the aquaculture industry has been significantly impacted by hepatopancreatic necrosis disease (HPND), leading to substantial economic losses. The exact cause and molecular mechanisms underlying HPND remain poorly understood.</p> Objective <p>This study aimed to decipher the genetic and molecular basis of HPND through an integrative transcriptomic meta-analysis to identity consistent and disease related gene expression patterns.</p> Methods <p>Publicly available RNA-Seq datasets from three different studies were systematically integrated and analyzed. Differentially expressed transcripts (DETs) were identified through meta-analysis, followed by functional annotation and enrichment analyses of Gene Ontology and KEGG pathways.</p> Results <p>The meta-analysis identified 571 DETs, including 245 up-regulated and 326 down-regulated transcripts in diseased hepatopancreas. Functional enrichment revealed significant disruptions in the pathways of protein modification, lipid metabolism, and vesicle-mediated transport. These processes are crucial for immune functions including pathogen detection, antigen presentation, cytokine secretion, and metabolic adaptation to stress in the hepatopancreas. Moreover, we found 11 novel DETs (6 up-regulated and 5 down-regulated), highlighting the ability of meta-analysis to uncover low-abundance or context-specific genes that may escape detection in individual studies.</p> Conclusions <p>Our study provides valuable insights into the causes and pathogenic mechanisms of HPND, identifies novel genetic factors and gene markers for detection, and offers a deeper understanding of the disease, highlighting potential biomarkers for its prevention in <i>E. sinensis</i> aquaculture.</p>