Excess reactive oxygen species production and free radical formation can lead to oxidative stress that can damage cells, tissues, and organs. Cellular oxidative stress is defined as the imbalance between ROS production and antioxidants. This imbalance can lead to malfunction or structure modification of major cellular molecules such as lipids, proteins, and DNAs. During oxidative stress conditions, DNA and protein structure modifications can lead to various diseases. Various antioxidant-specific gene expression and signal transduction pathways are activated during oxidative stress to maintain homeostasis and to protect organs from oxidative injury and damage. The liver is more vulnerable to oxidative conditions than other organs. Antioxidants, antioxidant-specific enzymes, and the regulation of the antioxidant responsive element (ARE) genes can act against chronic oxidative stress in the liver. ARE-mediated genes can act as the target site for averting/preventing liver diseases caused by oxidative stress. Identification of these ARE genes as markers will enable the early detection of liver diseases caused by oxidative conditions and help develop new therapeutic interventions. This literature review is focused on antioxidant-specific gene expression upon oxidative stress, the factors responsible for hepatic oxidative stress, liver response to redox signaling, oxidative stress and redox signaling in various liver diseases, and future aspects.

Reactive oxygen species (ROS) play a significant role in the survival and decline of various biological systems. In liver-related metabolic disorders such as steatohepatitis, ROS can act as both a cause and a consequence. Alcoholic steatohepatitis (ASH) and non-alcoholic steatohepatitis (NASH) are two distinct types of steatohepatitis. Recently, there has been growing interest in using medications that target ROS formation and reduce ROS levels as a therapeutic approach for oxidative stress-related liver disorders. Mammalian systems have developed various antioxidant defenses to protect against excessive ROS generation. These defenses modulate ROS through a series of reactions, limiting their potential impact. However, as the condition worsens, exogenous antioxidants become necessary to control ROS levels. Nanotechnology has emerged as a promising avenue, utilizing nanocomplex systems as efficient nano-antioxidants. These systems demonstrate enhanced delivery of antioxidants to the target site, minimizing leakage and improving targeting accuracy. Therefore, it is essential to explore the evolving field of nanotechnology as an effective means to lower ROS levels and establish efficient therapeutic interventions for oxidative stress-related liver disorders.

Fibroblast growth factor 23 (FGF23), a hormone generally derived from bone, is important in phosphate and vitamin D homeostasis. In acute kidney injury (AKI) patients, high-circulating FGF23 levels are associated with disease progression and mortality. However, the organ and cell type of FGF23 production in AKI and the molecular mechanism of its excessive production are still unidentified. For insight, we investigated folic acid (FA)-induced AKI in mice. Interestingly, simultaneous with FGF23, orphan nuclear receptor ERR-γ expression is increased in the liver of FA-treated mice, and ectopic overexpression of ERR-γ was sufficient to induce hepatic FGF23 production. In patients and in mice, AKI is accompanied by up-regulated systemic IL-6, which was previously identified as an upstream regulator of ERR-γ expression in the liver. Administration of IL-6 neutralizing antibody to FA-treated mice or of recombinant IL-6 to healthy mice confirms IL-6 as an upstream regulator of hepatic ERR-γ–mediated FGF23 production. A significant (P < 0.001) interconnection between high IL-6 and FGF23 levels as a predictor of AKI in patients that underwent cardiac surgery was also found, suggesting the clinical relevance of the finding. Finally, liver-specific depletion of ERR-γ or treatment with an inverse ERR-γ agonist decreased hepatic FGF23 expression and plasma FGF23 levels in mice with FA-induced AKI. Thus, inverse agonist of ERR-γ may represent a therapeutic strategy to reduce adverse plasma FGF23 levels in AKI. Significance Bone is the main source of fibroblast growth factor 23 (FGF23), which is important for phosphate and vitamin D homeostasis. In acute kidney injury (AKI), high blood levels of FGF23 are positively correlated with disease progression and increased risk of mortality. Reducing adverse plasma FGF23 levels in AKI patients is favorable. We showed here that hepatocytes are the major source of circulating FGF23, and orphan nuclear receptor ERR-γ is a novel transcriptional regulator of hepatic FGF23 production in AKI. Liver-specific depletion of ERR-γ or ERR-γ inverse agonist, GSK5182, significantly reduced plasma levels of FGF23 in AKI. This study reveals liver is the source of FGF23 and a therapeutic strategy to control pathologically adverse plasma FGF23 levels in AKI.

Postmenopausal osteoporosis is caused by estrogen deficiency, which impairs bone homeostasis, resulting in increased osteoclastic resorption without a corresponding increase in osteoblastic activity. Postbiotics have several therapeutic properties, including anti-obesity, anti-diabetic, anti-inflammatory, and anti-osteoporotic effects. However, the beneficial effects of the postbiotic MD35 of Lactobacillus plantarum on bone have not been studied. In this study, we demonstrated that the postbiotic L. plantarum MD35, isolated from young radish water kimchi, influences osteoclast differentiation in mouse bone marrow-derived macrophage (BMM) culture. In addition, it was effective protecting against estrogen deficiency-induced bone loss in ovariectomized (OVX) mice, an animal model of postmenopausal osteoporosis. In BMM cells, postbiotic MD35 inhibited the receptor activator of nuclear factor-kappa B of NF-κB ligand (RANKL)-induced osteoclast differentiation by attenuating the phosphorylation of extracellular signal-related kinase, significantly suppressing the resorption activity and down-regulating the expression of RANKL-mediated osteoclast-related genes. In the animal model, the oral administration of postbiotic MD35 remarkably improved OVX-induced trabecular bone loss and alleviated the destruction of femoral plate growth. Therefore, postbiotic MD35 could be a potential therapeutic candidate for postmenopausal osteoporosis by suppressing osteoclastogenesis through the regulation of osteoclast-related molecular mechanisms.