The NR3B subfamily of orphan nuclear receptors contains three members: estrogen-related receptor α, β, and γ (ERRα, ERRβ, and ERRγ). These constitutively active nuclear receptors bind to the classical estrogen response element TCAAGGTCA, referred to as the ERR response element (ERRE), located in the regulatory regions of their target genes (Tremblay and Giguère, 2007). Based on specific upstream signals, diverse membrane receptor signaling modulates ERRγ expression, subsequently influencing the expression of specific sets of target genes (Kim et al., 2011, 2012, 2013, 2014; Jung et al., 2021a; Radhakrishnan et al., 2020, 2021). ERRγ plays a pivotal role in a wide range of physiological and pathological processes, including hepatic gluconeogenesis, angiogenesis, iron homeostasis, pancreatic β-cell maturation, insulin signaling, lipid and cholesterol metabolism, vascular calcification, cardiac mitochondrial function, endoplasmic reticulum (ER) stress, and liver injuries (Misra et al., 2017). In the context of liver injury, ERRγ has been shown to regulate hepatic oxidative stress responses, mitochondrial dysfunction, and the expression of inflammation-associated genes, contributing to both the progression and modulation of liver damage (Kim et al., 2013; Misra et al., 2017; Jung et al., 2023). Its expression is upregulated in models of alcoholic liver disease and drug-induced hepatotoxicity, where it governs the transcription of genes such as CYP2E1 and FGF23 that exacerbate oxidative stress and hepatocyte damage (Kim et al., 2013; Jung et al., 2023). Moreover, ERRγ activity influences metabolic reprogramming and hepatocyte survival pathways, suggesting it plays a context-dependent role in either promoting or mitigating liver pathology. Given its highly inducible and targetable nature as a transcription factor, manipulating ERRγ expression emerges as an effective strategy for controlling these conditions (Huss et al., 2015). The transcriptional activity of ERRγ heavily depends on its interaction with co-activators or co-repressors through the C-terminal AF-2 domain within the ligand-binding domain (LBD) (Sasidharan et al., 2023). The ERRγ-specific inverse agonist, GSK5182, is extensively employed to control the transcriptional activity of ERRγ (Chao et al., 2006). Within the liver, ERRγ not only regulates the expression of genes linked to liver pathogenesis but also modulates the expression of favorable genes as part of the liver's compensatory response (Jung et al., 2016).

Growth differentiation factor 15 (GDF15) is a pleiotropic cytokine belonging to the superfamily of transforming growth factor β (TGF-β), a large family of soluble factors that regulate embryonic development and tissue homeostasis. GDF15 was first cloned by Bootcov et al. in 1997 as a gene enriched in activated macrophages and initially termed macrophage inhibitory cytokine-1 (MIC-1) (Bootcov et al., 1997). Over successive years, various research groups independently cloned the same gene, each assigning it different names, with the widely recognized name GDF15 emerging over time. It is produced as an inactive precursor, pre-pro-GDF15, which undergoes cleavage of the N-terminal signal peptide to form pro-GDF15. The mature and biologically active GDF15, detectable in circulation, results from the proteolytic cleavage of dimeric pro-GDF15 (Wang and Day, 2021). It is expressed across diverse tissues, including the placenta, liver, intestine, adipose tissue, skeletal muscle, lung, kidneys, and neuroepithelium (Wang and Day, 2021; Hsiao et al., 2000; Coll et al., 2020; Paralkar et al., 1998; Yokoyama-Kobayashi et al., 1997; Schober et al., 2001; Bauskin et al., 2006). Under normal physiology, the receptor signaling and functional role of GDF15 remain poorly defined. In pathophysiological states, circulatory levels of GDF15 considerably increase in various conditions ranging from metabolic diseases to mitochondrial disorders and cancers (Welsh et al., 2003; Kempf et al., 2007, 2012; Fujita et al., 2015; Nair et al., 2017; Lee et al., 2017; Chung et al., 2017a). In liver injury models, both acute and chronic, GDF15 is strongly induced in hepatocytes and non-parenchymal liver cells. Its upregulation has been associated with anti-inflammatory and cytoprotective effects, limiting immune-mediated damage and fibrosis progression (Kim et al., 2018; Zimmers et al., 2006). Moreover, studies in GDF15-deficient mice have demonstrated worsened liver pathology following toxic injury or diet-induced steatohepatitis, highlighting its hepatoprotective role (Chung et al., 2017a). Specifically, GDF15 has been shown to activate AMP-activated protein kinase (AMPK) and inhibit gluconeogenesis and fibrosis in the liver by attenuating the TGF-β1/SMAD3 signaling pathway (Jurado-Aguilar et al., 2024). Additionally, GDF15 ameliorates liver fibrosis by promoting the metabolic reprogramming of macrophages toward an anti-inflammatory phenotype, thereby reducing hepatic inflammation and fibrogenesis (Li et al., 2023). Furthermore, GDF15 prevents lipopolysaccharide (LPS) and D-galactosamine-induced inflammation and acute liver injury in mice (Li et al., 2018), underscoring its protective role in hepatic inflammatory responses.

Elevated GDF15 levels associated with disease conditions are not a cause but rather a compensatory mechanism, defending tissues from further damage. The well-documented protective role of GDF15 against diseases affecting various organs highlights its potential as an attractive therapeutic strategy. Consequently, GDF15 holds promise for addressing a broad spectrum of conditions, including obesity, diabetes, inflammatory diseases, mitochondrial disorders, renal failure, thalassemia, vascular diseases, sickle cell anemia, and liver diseases (Wang and Day, 2021; Chung et al., 2017a; Kim et al., 2018; Sjøberg et al., 2023; Breit et al., 2011, 2023). Despite the significant implication of GDF15 in a wide range of diseases, the precise molecular mechanisms governing its gene expression and production remain elusive.

Acute and chronic liver injuries are two distinct forms of liver damage with varying pathophysiological mechanisms and clinical implications. Acute liver injury is characterized by a sudden onset of liver damage, typically caused by exposure to hepatotoxic substances or acute viral infections. This condition often manifests as severe hepatocellular necrosis and inflammation, leading to rapid impairment of liver function. Chronic liver injury often develops over a period of several months or years and is commonly associated with conditions such as chronic alcohol abuse, viral hepatitis, or metabolic disorders. Carbon tetrachloride (CCl4) administration and alcohol intoxication are well-established models used to induce acute and chronic liver injury, respectively, in experimental studies.

In this study, our findings substantiate the role of the orphan nuclear receptor ERRγ in regulating hepatic gene expression and the secretion of GDF15 in mice subjected to both acute and chronic liver injury induced by CC14 administration and alcohol intoxication, respectively. Moreover, we have disclosed a detailed molecular mechanism underlying the ERRγ-mediated transcriptional regulation of GDF15 production within the liver.