Schisandrae Chinensis Fructus (SF), a cornerstone of traditional Chinese medicine (TCM), is recognized for its ability to invigorate “Qi” within the Liver zang and other “visceral organs” via the meridian system [1]. In TCM, the Liver’s pivotal role as a “General” organ, orchestrating the functions of numerous other visceral organs, provides a theoretical framework for SF’s broad health-promoting effects [2]. The principal bioactive compound within SF, schisandrin B (Sch B), has demonstrated promising effects, including improved mitochondrial ATP production and enhanced glutathione redox status across various organs [3][4]. These findings suggest that Sch B’s organ-protective properties may stem from its influence on cellular energy metabolism and antioxidant defense. Given Sch B’s pronounced impact on liver function, it is plausible that its beneficial effects on other organs are mediated by signaling molecules originating from the liver. This study investigates whether Sch B can positively alter plasma glutathione redox status and modulate the levels of hepatokines—liver-secreted proteins that influence cardiometabolic function—to exert its regulatory effects on extrahepatic tissues.

Previous research has established that Sch B treatment enhances the hepatic GSH to GSSG ratio, thereby improving liver glutathione redox status [3]. Our current findings extend this observation to the systemic circulation, demonstrating that Sch B treatment also significantly improves plasma glutathione redox status, which is mediated by decreasing circulating GSSG levels (data not shown). This elevation of glutathione redox status is crucial, as it sustains the transport of plasma GSH to extrahepatic tissues, such as cardiac and skeletal muscle. The increase in plasma glutathione redox reflects the liver’s ability to replenish plasma GSH that has been delivered to tissues [7][8]. In these tissues, the increased GSH bolsters cellular antioxidant defenses, which are particularly vital for sustaining high-energy metabolic states [7]-[10].

Glutathione, the body’s master antioxidant, relies on the delicate balance of its GSH/GSSG ratio as a key indicator of cellular redox health [9]-[11]. Naturally occurring aging in mice is typically characterized by a progressive decline in this ratio, leading to the accumulation of oxidative damage across various tissues [12]. By elevating the GSH/GSSG ratio in the blood, Sch B treatment effectively counteracts this age-related decline in tissue GSH levels. This strengthens the body’s capacity to neutralize reactive oxygen species, thereby safeguarding critical tissues such as the brain and cardiovascular system from the damaging oxidative stress associated with elevated metabolic activity. This systemic antioxidant enhancement is further supported by prior research demonstrating that long-term Sch B administration can suppress age-associated reductions in mitochondrial GSH levels in diverse tissues, including the liver, brain, heart, and kidneys, ultimately contributing to an extended average lifespan [13].

Beyond its potent antioxidant effects, Sch B treatment also significantly modulated the hepatokine profile. Specifically, we observed a decrease in the levels of ANGPTL3 and ANGPTL4, accompanied by an increase in adropin (Table 1). The dual suppression of ANGPTL3 and ANGPTL4 is particularly noteworthy for its potential cardiovascular benefits [14]. These proteins are known inhibitors of lipoprotein lipase and endothelial lipase; their reduction can therefore maximize the activity of these enzymes, leading to a substantial decrease in plasma triglycerides and circulating low-density lipoprotein cholesterol [15][16]. Indeed, studies in mouse models have shown that downregulating these specific angiopoietin-like proteins can halt the progression of atherosclerosis, reduce vascular inflammation, and diminish the size of necrotic core areas within arterial plaques [17][18].

Concurrently, the elevated level of adropin is poised to powerfully stimulate energy utilization and prevent the spontaneous development of obesity and insulin resistance [19][20]. Adropin complements these effects by functioning as an insulin-sensitizing hormone that protects the liver from excessive fat accumulation [21][22]. Collectively, these modulated hepatokines orchestrate a significant metabolic shift within the body, promoting a state of enhanced efficiency characterized by increased fat burning and improved glucose utilization.

One limitation of the present study was that only male mice were used. However, prior studies indicated no gender difference in various Sch B-induced pharmacological actions.

Table 1. Effects of Sch B treatment on glutathione redox status and hepatokine levels in plasma of mice. Values given are mean % control ± SD (n = 5). Control values: GSH/GSSG ratio, 3.35 ± 0.31; ANGPTL3 (ng/mL), 7.82 ± 0.44; ANGPTL4 (ng/mL), 3.17 ± 0.79; adropin (μg/mL), 20.1 ± 2.16. *p < 0.05, when compared to the control value, using One-way ANOVA (LSD test).

This study provides compelling evidence that Sch B exerts its beneficial metabolic effects through a dual mechanism: direct antioxidant actions and the orchestration of a systemic shift in liver-derived signaling. By enhancing plasma glutathione redox status, Sch B bolsters antioxidant defenses in vital extrahepatic tissues, counteracting age-related oxidative damage. Furthermore, the modulation of key hepatokines, specifically the suppression of ANGPTL3 and ANGPTL4 alongside the elevation of adropin, reveals a sophisticated metabolic regulatory pathway. These combined actions collectively promote a healthier lipid profile, reduce cardiovascular risk factors, and foster a metabolic environment conducive to energy expenditure and improved insulin sensitivity. These findings underscore the potential of Sch B as a nutraceutical or therapeutic agent for metabolic disorders, highlighting the intricate interplay between liver function and systemic metabolic health.