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Simple Summary We recently reported that the human TOR signaling regulator (hereafter TIPRL) contributes to the drug-resistance of hepatocellular carcinomas (HCCs) and the involvement of TIPRL/LC3/CD133 in liver cancer aggressiveness. This study aims to determine prognostic and diagnostic efficacies of TIPRL/LC3/CD133/CD44 for early liver cancer. We observed the significant upregulation of TIPRL and LC3 in HCCs and adult hepatocyte-derived liver disease while observing downregulation in intrahepatic carcinomas (iCCA). The TIPRL level has been shown to be the clearest indicator of liver cancer patients’ survivability as a sole covariate. This indication supports that TIPRL contributed to liver cancer cell proliferation and survival via stemness and self-renewal induction. TIPRL/LC3/CD133 have exhibited crucial efficiency in diagnostic patients with grade 1 iCCA, and TIPRL/LC3/CD133/CD44 showed prognosticating grade-1 HCCs and iCCA, either as an alone or in conjunction. Overall, this study reports that TIPRL/LC3/CD133/CD44 could, either individually or in conjunction, serve as potential biomarkers for early liver cancer. Abstract Recently, we reported the involvement of TIPRL/LC3/CD133 in liver cancer aggressiveness. This study assessed the human TOR signaling regulator (TIPRL)/microtubule-associated light chain 3 (LC3)/prominin-1 (CD133)/cluster of differentiation 44 (CD44) as potential diagnostic and prognostic biomarkers for early liver cancer. For the assessment, we stained tissues of human liver disease/cancer with antibodies against TIPRL/LC3/CD133/CD44/CD46, followed by confocal observation. The roles of TIPRL/LC3/CD133/CD44/CD46 in liver normal and cancer cell lines were determined by in vitro studies. We analyzed the prognostic and diagnostic potentials of TIPRL/LC3/CD133/CD44/CD46 using the receiver-operating characteristic curve, a Kaplan–Meier and uni-/multi-Cox analyses. TIPRL and LC3 were upregulated in tissues of HCCs and adult hepatocytes-derived liver diseases while downregulated in iCCA. Intriguingly, TIPRL levels were found to be critically associated with liver cancer patients’ survivability, and TIPRL is the key player in liver cancer cell proliferation and viability via stemness and self-renewal induction. Furthermore, we demonstrate that TIPRL/LC3/CD133 have shown prominent efficiency for diagnosing patients with grade 1 iCCA. TIPRL/LC3/CD133/CD44 have also provided excellent potential for prognosticating patients with grade 1 iCCA and grade 1 HCCs, together with demonstrating that TIPRL/LC3/CD133/CD44 are, either individually or in conjunction, potential biomarkers for early liver cancer. more...