biostudies-literatureDing PNatural Science Foundation of Anhui Province (Anhui Provincial Natural Science Foundation)University Natural Science Research Project of Anhui Province (Anhui Provincial Universities Natural Science Research Project)National Natural Science Foundation of China (National Science Foundation of China)314https://www.ebi.ac.uk/biostudies/studies/S-EPMC12936196biostudies-literatureUnknown9(1)Hepatocellular carcinoma (HCC) is a highly lethal malignancy, with epithelial-mesenchymal transition (EMT)-driven metastasis a key factor for poor prognosis. The C5a/C5a receptor (C5aR) pathway significantly facilitates HCC cell EMT, yet no approved anti-cancer drugs specifically target C5aR. LukS-PV, a component of Staphylococcus aureus-secreted Panton-Valentine leukocidin (PVL), specifically targets C5aR and exerts anti-tumor effects in hematological and solid tumors. However, its impact on HCC EMT and mechanisms remains unknown. Our study showed LukS-PV targets C5aR to inhibit HCC cell EMT, migration, invasion, and in vivo lung metastasis. Mechanistically, LukS-PV downregulates B-cell lymphoma 6 (BCL6), reducing histone deacetylase 6 (HDAC6) expression. Decreased HDAC6 increases heat shCommunications biologyLukS-PV targeting C5aR inhibits EMT in hepatocellular carcinoma via the BCL6/HDAC6/HSPD1 axis.PMC1293619681972001822034362208085QH2502023AH05340382102478Shi LNie ZMa XDing PWang XXu XWang YZhang SDai YLu BLiu GChang WfalseLukS-PV targeting C5aR inhibits EMT in hepatocellular carcinoma via the BCL6/HDAC6/HSPD1 axis.Hepatocellular carcinoma (HCC) is a highly lethal malignancy, with epithelial-mesenchymal transition (EMT)-driven metastasis a key factor for poor prognosis. The C5a/C5a receptor (C5aR) pathway significantly facilitates HCC cell EMT, yet no approved anti-cancer drugs specifically target C5aR. LukS-PV, a component of Staphylococcus aureus-secreted Panton-Valentine leukocidin (PVL), specifically targets C5aR and exerts anti-tumor effects in hematological and solid tumors. However, its impact on HCC EMT and mechanisms remains unknown. Our study showed LukS-PV targets C5aR to inhibit HCC cell EMT, migration, invasion, and in vivo lung metastasis. Mechanistically, LukS-PV downregulates B-cell lymphoma 6 (BCL6), reducing histone deacetylase 6 (HDAC6) expression. Decreased HDAC6 increases heat sh2026-01-01T00:00:00Z2026 Jan2026-07-16T21:54:54.657Z2026-07-12T03:06:41.466ZS-EPMC129361964161809310.1038/s42003-026-09640-9