Background and Aims Hepatocellular carcinoma (HCC) is characterized by high invasiveness, frequent recurrence, and poor clinical prognosis. The molecular mechanisms underlying the occurrence and development of HCC remain unclear. Phosphatidylinositol transfer protein cytoplasmic 1 (PITPNC1) is a lipid metabolism-related gene shown to promote cancer. However, the role of PITPNC1 in the development of HCC remains unknown. Thus, this study aimed to investigate the expression and function of PITPNC1 in HCC.Methods A prospective cohort study was conducted on 116 patients with HCC who underwent liver resection surgery at Xiangya Hospital, Central South University, from January 2015 to December 2018. Patient medical records and tissue specimens were collected, and regular follow-ups were performed. Immunohistochemistry was used to detect PITPNC1 protein expression in patient tissue samples, and the relations of PITPNC1 expression with clinicopathologic features and prognosis were analyzed. The expression of PITPNC1 in human HCC cell lines was analyzed using the LCCLD database. Lentivirus-mediated small RNA interference was utilized to silence PITPNC1 expression in the highly invasive and metastatic HCC cell line MHCC97H. Colony formation and subcutaneous tumor experiments were performed to observe the relationship between PITPNC1 expression and HCC growth, and Oil Red O staining was conducted on the subcutaneous xenografts. Bioinformatics analysis was used to investigate the molecular mechanisms of PITPNC1 action.Results The PITPNC1 protein was positively stained in the cytoplasm, with a positive expression rate of 76.7% (88/116) in tumor tissues and 21.5% (24/116) in adjacent non-tumor liver tissues, and the difference was statistically significant (P<0.001). High PITPNC1 expression was significantly associated with satellite nodules (P=0.041), vascular invasion (P<0.001), tumor differentiation (P=0.027), BCLC stage (P=0.009), and TNM stage (P=0.028). Kaplan-Meier survival analysis revealed that HCC patients with high PITPNC1 expression had significantly lower overall survival (OS) and recurrence-free survival (RFS) rates (both P<0.001); PITPNC1 expression was an independent factor influencing OS and RFS (HR=11.775, 95% CI=1.462-4.082, P=0.006; HR=1.928, 95% CI=1.306-4.889, P=0.004). After PITPNC1 silencing, both in vitro and in vivo growth of MHCC97H cells were significantly suppressed (both P<0.05). Oil Red O staining showed a significant reduction in lipid accumulation in the subcutaneous xenografts following PITPNC1 downregulation (P<0.05). Database analysis indicated that PITPNC1 overexpression was associated with lipid metabolism-related PPAR signaling pathway activity.Conclusion PITPNC1 is a novel oncogene and adverse prognostic marker in HCC. It may play a significant role in promoting HCC growth by regulating the lipid metabolism pathway.