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Cancer, Stress, Anesthesia, and Immune Response / Ferroptosis and Cancer Prognosis · Journal article
Biology Direct · September 10, 2026
Early or partial results. Treat as a signal, not a conclusion.
This preclinical study demonstrates that ciprofol, a propofol derivative, induces ferroptosis in hepatocellular carcinoma cells by suppressing USP1 and promoting GPX4 ubiquitination and degradation, with in vivo evidence of tumor growth reduction and enhanced anti-PD-1 efficacy in mouse models. The work establishes a plausible mechanistic rationale for combination therapy but remains exploratory and requires clinical translation.
Preclinical mechanistic study with in vitro cell line experiments and in vivo xenograft and syngeneic mouse models. Human hepatocellular carcinoma cell lines (Huh-7, MHCC97-H), mouse HCC cell line (H22), nude mice and C57BL/6 mice for in vivo studies. No eligibility criteria or clinical population enrolled.. Intervention: Ciprofol (a propofol derivative used in clinical anesthesia), administered at 40 mg/kg in vivo; combination with anti-PD-1 antibody in mouse models. Compared with: Ferroptosis inhibitor Fer-1, USP1 knockdown, and anti-PD-1 antibody monotherapy; untreated controls implied but not explicitly detailed. Not stated.
Ciprofol inhibited HCC cell proliferation with IC₅₀ of 43.7 µM for Huh-7 and 36.4 µM for MHCC97-H cell lines Ciprofol induced ferroptosis evidenced by increased ROS, Fe²⁺, MDA, and mitochondrial shrinkage/cristae disruption, reversed by ferroptosis inhibitor Fer-1 Ciprofol directly bound to USP1 with Kd = 1.5 µM and reduced USP1 expression, disrupting USP1-GPX4 interaction
No human clinical data, phase 1 trials, or pharmacokinetic/pharmacodynamic studies in humans reported Ciprofol has not been previously explored for cancer therapy; off-label use of anesthetic requires regulatory and safety assessment
While the mechanistic pathway is well-characterized preclinically, ciprofol remains investigational for HCC therapy with no human phase 1 or efficacy data yet available. Clinical translation and human trials would be needed to establish safety, tolerability, and therapeutic benefit in patients with HCC.
Mechanistic preclinical study with in vitro and mouse models showing ciprofol induces ferroptosis and enhances anti-PD-1 efficacy in HCC; no human clinical data or phase 1 trial reported, limiting evidence strength despite sound experimental design.
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While the mechanistic pathway is well-characterized preclinically, ciprofol remains investigational for HCC therapy with no human phase 1 or efficacy data yet available. Clinical translation and human trials would be needed to establish safety, tolerability, and therapeutic benefit in patients with HCC.
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Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have shown promise in hepatocellular carcinoma (HCC), but resistance due to the immunosuppressive tumor microenvironment remains a major challenge. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a potential strategy to enhance anti-tumor immunity. Ciprofol, a novel propofol derivative widely used in clinical anesthesia, has not been explored for its role in cancer therapy. In this study, we evaluated the anti‑proliferative and pro‑ferroptotic effects of ciprofol in human HCC cell lines (Huh‑7, MHCC97‑H) and a mouse HCC line (H22) using CCK‑8, EdU, colony formation, Transwell, and flow cytometry assays. Ferroptosis was assessed by measuring ROS, Fe²⁺, MDA, SOD, and mitochondrial morphology via TEM. Molecular mechanisms were investigated by Western blot, qRT‑PCR, Co‑IP, ubiquitination assay, and surface plasmon resonance (SPR). In vivo efficacy was examined in xenograft (nude mice) and syngeneic (C57BL/6) models, and combination therapy with anti‑PD‑1 antibody was evaluated. Ciprofol inhibited HCC cell proliferation, migration, invasion, and epithelial‑mesenchymal transition (EMT) (IC₅₀: 43.7 µM for Huh‑7; 36.4 µM for MHCC97‑H). Mechanistically, ciprofol induced ferroptosis, evidenced by increased ROS, Fe²⁺, MDA, and typical mitochondrial shrinkage/cristae disruption, which were reversed by the ferroptosis inhibitor Fer‑1. Ciprofol did not alter GPX4 mRNA levels but promoted its ubiquitination and proteasomal degradation. Transcriptome analysis identified USP1 as a key downstream target. Ciprofol reduced USP1 expression, disrupted the USP1‑GPX4 interaction, and directly bound to USP1 (Kd = 1.5 µM). USP1 knockdown phenocopied ciprofol effects, inducing ferroptosis and suppressing HCC progression. In vivo, ciprofol (40 mg/kg) significantly reduced tumor growth, downregulated USP1/GPX4, and was well‑tolerated. Importantly, ciprofol improved tumor control when combined with anti-PD-1 antibody. In conclusion, ciprofol is a novel ferroptosis inducer that promotes GPX4 ubiquitination and degradation by suppressing USP1, exhibits potent anti‑HCC activity, and enhances the therapeutic efficacy of anti‑PD‑1 immunotherapy, representing a promising sensitizer for combined cancer treatment. Not applicable.
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