AbstractThe microsporidia Hepatospora eriocheir has been identified as an emerging pathogenic agent in the commercial crab Eriocheir sinensis. Histology analysis indicated that hepatopancreas was a significant target for H. eriocheir infection. However, the functional consequences of such tissue tropism remain poorly studied. Considering that hepatopancreas was a centre for lipid metabolism and energy supply, we furtherly investigated the comparative lipid metabolism profiles between the control and H. eriocheir‐infected hepatopancreas by liquid chromatography–mass spectrometry (LC‐MS)‐based lipidomics approach. Results confirmed that H. eriocheir induced apparent alterations of lipid metabolic phenotypes in hepatopancreas. Sixty‐seven lipids, including triglyceride (TG), diglyceride (DG), sphingomyelin (SM), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylinositol (PI), ceramide (CER), hexosyl ceramide (HEX CER) and (o‐acyl)‐1‐hydroxy fatty acid (OAHFA), were significantly changed and could be determined as effective biomarkers. TG and DG accounted for the largest proportion (58.2% and 11.9%, respectively). Notably, over 94% of the distinguished lipids presented a similar modified trend with profoundly reduced contents, implying blatant energy exploitation of the parasite. These lipids were involved in pathways of energy and lipid metabolism and signal regulation. Such information suggests that H. eriocheir possibly “starves” the host via destructing hepatopancreas tissue together with appropriate host energy resources, leading to the corresponding alterations of lipid metabolism and a decrease in the colour of the hepatopancreas.