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Background: Earlier, we showed the possibility of potency classification of promising peroxisome proliferator-activated receptor (PPAR)-agonists for anti-non-alcoholic steatohepatitis (NASH) treatment using human-derived hepatic in vitro disease models including primary human hepatocytes (PHH), human skin stem cell-derived hepatic progenitors (hSKP-HPC) and cancer cell lines (HepaRG, HepG2). Among those PPAR-agonists, elafibranor, followed by saroglitazar and pioglitazone showed the strongest anti-NASH potencies in vitro. Elafibranor, however, recently failed to show sufficient efficacy in a phase III clinical trial interim analysis and its development was discontinued. Therefore, we aimed to investigate possible molecular mechanisms that could lay at the basis of this failure. Methods: PHH, hSKP-HPC and HepaRG cultures were exposed to NASH-inducing triggers (insulin, glucose, sodium oleate, palmitic acid, TNF-α, IL-1β and TGF-β) with or without elafibranor for 24h. Hereafter, whole-genome microarrays (Affymetrix) were performed and used for pathway analysis. Publicly-available transcriptomic data of clinical samples of NASH patients and patients with resolved NASH after bariatric surgery served as benchmarks. Results: Hepatic ‘NASH-induced’ cultures showed up to 35% overlap with transcriptional signatures present in samples of NASH patients, indicating the relevance of the in vitro models. In all in vitro models, elafibranor restricted NASH-specific cellular processes through the activation and inhibition of processes also seen in pre- and post- bariatric surgery samples of NASH patients. PPARGC1A, PPARA and SIRT1 were identified as common upstream regulators in the three in vitro models exposed to elafibranor. Elafibranor induced upregulation of PLIN2, PDK4 and ANGPTL4, which have been earlier linked to liver steatosis, under regulation of the common upstream regulators. These pro-steatogenic mediators were, however, not increased in liver samples of patients with resolved NASH. Conclusions: Modulations of ANGPTL4, PDK4 and PLIN2 deserve further attention in the preclinical investigation of PPAR-agonists for the treatment of NASH.