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Dynamic Proteomic Analysis of Human Liver Organoids: Optimal Maturation Stage for Drug Metabolism and Toxicology Applications

ABSTRACT: Liver organoids have emerged as an innovative three-dimensional model system that effectively recapitulates the structural and functional complexities of human liver tissue, addressing critical limitations associated with traditional two-dimensional culture systems. This study presents a comprehensive temporal proteomic characterization of induced human liver organoids (iHLOs) by profiling 5,736 proteins across their four developmental stages Day 7, Day 15, Day 30, and Day 45 to identify optimal timepoints for drug metabolism and toxicological applications. The analysis revealed that Day 30 represents the peak of functional maturity, marked by the highest expression of key-metabolizing enzymes, such as cytochrome P450 3A4 (CYP3A4), along with cholangiocyte-specific proteins and hepatic metabolic enzymes. Functional validation of CYP3A4 activity through induction with rifampicin and inhibition with ketoconazole demonstrated comparable metabolic competence to existing in vitro liver models, including HepaRG cells and primary human hepatocytes. Interestingly, Day 45 organoids exhibited a shift toward a mesenchymal cell profile, with increased markers of hepatic stellate cells, suggesting utility in disease modeling applications. These findings suggest Day 30 of liver organoids as the optimal stage for drug metabolism and toxicological investigations, providing a proteomic framework that enhances the functional utility of iHLOs as physiologically relevant liver models.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatocyte, Cell Culture

SUBMITTER: Jon (Jian-Jiang) Hao

LAB HEAD: Menghang Xia

PROVIDER: PXD063438 | Pride | 2026-01-16

REPOSITORIES: Pride

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			Action	DRS
	P1211R-A-ECT32-18PLEX-F.msf	Msf
	P1211R-A-ECT32-18PLEX-F.msfView	Msf
	P1211R-A-ECT32-18PLEX-F.mzML	Mzml
	P1211R-A-ECT32-18PLEX-F.mzid	Mzid
	P1211R-A-ECT32-18PLEX-F.pdResult	Other

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Project description:The main constituents of electronic cigarette liquids are nicotine, propylene glycol (PG), and vegetable glycerin (VG), together with distilled water and flavors. To assess the toxicity of PG/VG mixtures with and without nicotine as basic components of liquids used in e-cigarettes, a 90-day rat inhalation study according to the Organization for Economic Co-operation and Development test guideline 413 was conducted. Sprague-Dawley (SD) rats were nose-only exposed, 6 h/day, 5 days/week to filtered air, or nebulized vehicle (saline), or three concentrations of PG/VG (0.174 mg PG/l + 0.210 mg VG/l; 0.520 mg PG/l + 0.630 mg VG/l; 1.520 mg PG/l + 1.890 mg VG/l) – with (test item) and without (reference item) 23 µg nicotine/L. Standard toxicological endpoints were complemented by molecular analyses using transcriptomics, proteomics, and lipidomics. Compared to vehicle exposure, the tested PG/VG aerosols showed only very limited biological effects with no signs of toxicity, both for the standard toxicological endpoints (e.g., histopathology, clinical chemistry) and the systems toxicological analyses (transcriptomics, proteomics, and lipidomics). The addition of nicotine to the PG/VG aerosols (23 µg/l) resulted in effects in line with nicotine effects in previous studies. These included up-regulation of xenobiotic enzymes (Cyp1a1 and Fmo3) in the lung and metabolic effects, e.g., reduction in serum lipid concentrations and changes in the expression of metabolic enzymes in the liver. Signs of a generalized stress response to nicotine exposure such as decreased thymus weights were observed; and likely, a subset of the observed metabolic alterations was interlinked with this generalized stress response. Under the conditions of this 90-day SD rat inhalation study, no toxicologically relevant effects of PG/VG aerosols (up to 1.520 mg PG/l + 1.890 mg VG/l) were observed, and the no observed adverse effect level (NOAEL) for PG/VG/nicotine was determined to be 438/544/6.7 mg/kg/day. Further the study demonstrated how complementary systems toxicology analyses can reveal, also in the absence of observable adverse effects, subtoxic and adaptive responses to pharmacologically active compounds such as nicotine.

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Dynamic Proteomic Analysis of Human Liver Organoids: Optimal Maturation Stage for Drug Metabolism and Toxicology Applications

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