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ARTICLE

Phenotypic Response Surfaces–Guided Optimization (PRS-OPT) of Propolis-Metformin-Regorafenib Combination Therapy for MASLD-Associated Hepatocellular Carcinoma

Yi-Sian Huang1,2, Chung-Yung Ma1,2, Hsiao-Yuh Roan3, Cheng-Hsiung Chiang4, Hsiao-Hui Tsou4, Chen-Hui Chen3, Yi-Fan Lin2, Horng-Dar Wang2, Chiou-Hwa Yuh1,5,6,7,*
1 Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, Taiwan
2 Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan
3 Institute of Cellular and Organismic Biology, Academia Sinica, Nankang, Taipei, Taiwan
4 Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Miaoli, Taiwan
5 Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan
6 Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
7 Program in Environmental and Occupational Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
* Corresponding Author: Chiou-Hwa Yuh. Email: email
(This article belongs to the Special Issue: AI-Guided Phenotypic Response Surfaces for Precision Oncology: From Model Systems to Clinical Dosing)

Oncology Research https://doi.org/10.32604/or.2026.074145

Received 03 October 2025; Accepted 09 March 2026; Published online 03 April 2026

Abstract

Objectives: Hepatocellular carcinoma (HCC) arising in metabolic dysfunction–associated steatotic liver disease (MASLD) develops under lipid-rich stress and inflammatory remodeling, which can alter therapeutic windows. We aimed to determine whether phenotypic response surface–guided optimization (PRS-OPT) can nominate hepatocyte-sparing propolis–metformin–regorafenib (PMR) dose windows that retain antitumor activity under MASLD-like fatty-acid (FA) stress and translate to an in vivo immune endpoint. Methods: PMR combinations were profiled in hepatoma cell lines (PLC/PRF/5 and HepG2) and non-malignant hepatocytes (THLE-2) under FA-free and FA-enriched conditions. Quadratic response surfaces were fitted and used for constrained dose nomination, followed by in vitro validation. Cell-death contributions were assessed by inhibitor-rescue, Annexin V/PI flow cytometry, and immunoblotting. PRS-OPT was extended to zebrafish MASLD-HCC to optimize dosing against hepatic macrophage accumulation, with longitudinal imaging and qPCR endpoints. Results: FA exposure shifted the feasible efficacy–tolerability landscape, leading PRS-OPT to nominate a distinct FA-optimized PMR window with improved hepatocyte preservation while maintaining tumor suppression. Validation confirmed tumor-preferential activity across hepatoma lines with hepatocyte sparing. Mechanistic assays supported apoptosis with context dependence and evidence consistent with a ferroptosis-related component in HepG2. In zebrafish MASLD-HCC, PRS-OPT–nominated dosing reduced hepatic macrophage accumulation and improved disease-relevant transcriptional and morphological readouts. Conclusions: PRS-OPT enables interpretable, multi-objective dose nomination for MASLD-relevant HCC contexts, and establishes PRS-OPT as an interpretable, multi-objective framework for regimen nomination that is directly extensible to additional phenotypic endpoints for preclinical evaluation.

Keywords

hepatocellular carcinoma; metabolic dysfunction–associated steatotic liver disease (MASLD); zebrafish; macrophages; phenotypic response surface-guided optimization (PRS-OPT)

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