I. Introduction
Historically, the seeds of Psoralea corylifolia L. <Figure 1A> have been used across East Asia not only as a medicinal herb but also as a health-enhancing dietary ingredient, commonly prepared as herbal tea or mild decoctions as part of daily health practices. Similar dietary and healthpromoting uses have also been documented in South Asian traditions, suggesting that Psoralea corylifolia L. represents an early form of functional food with diverse health benefits. In Korea, the seeds of Psoralea corylifolia L., are also known as Bo-Gol-Zhee, have long appeared in traditional prescriptions for musculoskeletal weakness and skin diseases (Kim et al. 2016) and were occasionally brewed as a functional tea to support vitality and bone health. In modern research, attention has increasingly shifted toward the bioactive constituents of Bo-Gol-Zhee, particularly prenylated flavonoids such as bavachin, isobavachalcone, and bavachinin (BVC) <Figure 1A>, which exhibit diverse biological activities including anti-inflammatory, anti-asthmatic, antioxidant, and metabolic regulatory effects. In particular, BVC has been reported to act as a PPARγ agonist, exerting beneficial effects on glucose and lipid metabolism in obesity and diabetes models (Zeng et al. 2025).
PPARγ is a ligand-activated transcription factor that functions as a master regulator of adipocyte differentiation and plays a central role in lipid storage, insulin sensitivity, and adipose tissue remodeling. Activation of PPARγ by synthetic agonists such as thiazolidinediones (TZDs) improves insulin sensitivity but is also well known to carry adverse effects including excessive adipogenesis, weight gain, fluid retention, and most notably, decreased osteoblast differentiation and bone loss (Schwartz 2006;Chang et al. 2014). Thus, naturally derived PPARγ ligands have been proposed as alternative modulators capable of preserving metabolic benefits while reducing the risk of skeletal adverse effects. Nonetheless, it remains essential to experimentally determine whether each candidate compound indeed demonstrates this desirable dual profile.
Therefore, in this study, we investigated BVC as a natural PPARγ ligand and confirmed the effect of BVC in stem cell differentiation of human mesenchymal stem cells (hMSCs). Adipogenic and bone-healing capacity were also analyzed using in vivo model. Through these analyses, we sought to clarify both the therapeutic potential and the possible adverse skeletal effects of BVC.
II. Materials and Methods
1. Materials
Bavachinin was purchased from Chromadex, Inc (Longmont, CO, USA). Dexamethasone, 3-isobutyl-1-methylxanthine (IBMX), rosiglitazone, insulin, ascorbic-2-phosphate, β- Glycerophosphate, Oil Red O, Alizarin Red S, and phorbol 12-myristate 13-acetate (PMA) were purchased from Sigma- Aldrich.
2. Adipogenic induction and Oil Red O staining
hMSCs were isolated in previous study (Lim et al. 2012) and maintained in α-MEM containing 10% FBS and penicillin-streptomycin at 37°C in 5% CO2. Cells at near confluence were detached with 0.25% trypsin and passaged at 5,000 cells/cm2. For adipogenesis, hMSCs at confluence were induced with adipogenic induction medium (AIM, 10% FBS, 1 μmol/L dexamethasone, 0.5 mmol/L IBMX, 1 μmol/ L insulin, and 1 μmol/L rosiglitazone in α-MEM) for 4 days, followed by maintenance medium containing 10% FBS and insulin. Lipid accumulation was assessed by Oil Red O staining after fixation with 4% paraformaldehyde. For quantification, the dye was extracted with isopropanol and absorbance was measured at 495 nm.
3. Osteogenic induction and Alizarin Red S staining
hMSCs at confluence were cultured for 21 days in osteogenic induction medium (OIM, 10% FBS, 100 nmol/L dexamethasone, 50 μmol/L ascorbic acid-2-phosphate and 10 mmol/L β-Glycerophosphate in α-MEM). Mineralization was evaluated by Alizarin Red S staining after fixation. To quantify the mineralization, stained Alizarin Red S was extracted using acetic acid and the absorbance was measured at 405 nm.
4. Rodents
C57BL/6 mice and Lewis rats (Orient Bio, Korea) and BALB/cSlc-nu/nu mice (Central Lab. Animal Inc, Korea) were housed under a 12 hours light-dark cycle in the Animal Research Facility at Ulsan National Institute of Science and Technology (UNIST) under specific pathogen-free conditions and given access to standard chow diet (A03, Scientific Animal Food & Engineering, Augy, France) or 60 kcal % fat diet (D12492, Research diets) and water ad libitum. Male animals were used for adipose tissue and bone regeneration experiments. All procedures were approved by the UNIST IACUC and performed according to institutional guidelines.
5. RNA extraction and quantitative RT-PCR
Total RNA was extracted using an easy-BLUE Total RNA extraction kit (iNtRON, South Korea). cDNA was synthesized from 1.5 μg of RNA using oligo(dT) primers and M-MLV reverse transcriptase (Promega). qPCR was performed using SYBR Premix Ex TaqTM (Takara) on a CFX96 system. Expression levels of each mRNA were compared after normalization to RPLP0.
6. Western blotting
Cell lysates were prepared using Triton X-100-based lysis buffer containing protease and phosphatase inhibitors. Proteins were separated on 8% or 12% SDS-PAGE gels and transferred to nitrocellulose membranes. After 5% skim milk blocking, membranes were probed with antibodies against PPARγ (sc-7273), phospho-PPARγ S273 (kindly provided by Professor Jang Hyun Choi at UNIST) (Choi et al. 2016), aP2 (sc-18661), or β-actin (GTX629630) followed by HRPconjugated secondary antibodies. Detection was performed using ECL (Amersham).
7. De novo fat pad formation
De novo fat pad formation was performed as previously described (Kawaguchi et al. 1998) with minor modifications. 3T3-F442A preadipocytes (1×107 cells; kindly provided by Dr. Schwartz, University of Michigan) were suspended in PBS and injected subcutaneously into the flanks of 6-weekold BALB/c nude mice. Animals received BVC (5 mg/kg/ day, i.p.) or vehicle (5% Tween-80) for 2 weeks. Fat pads were collected, fixed in 4% paraformaldehyde, paraffinembedded, sectioned, and stained with H&E.
8. Bone regeneration in rat calvarial defect model
Bone regeneration was evaluated using a rat calvarial defect model (Jang et al. 2020). Under anesthesia, 4-mm bilateral calvarial defects were created in 12-week-old male Lewis rats using a trephine bur with saline irrigation. Collagen membranes (GENOSS, South Korea) absorbing test molecules were implanted, and wounds were sutured. After 5 weeks, the defective sites were analyzed using a SkyScan 1176 μCT (75 kV, 333 μA, 1.0-mm aluminum filter). Images were reconstructed (NRecon) and bone regeneration quantified (CTAn) as the percentage of new bone volume (BV) relative to total defect volume (TV).
9. Statistical analysis
Data are presented as mean±standard errors (SE) as indicated in the figure legends. Comparisons between two groups were made by unpaired two-tailed Student’s t tests. P values of <0.05 were considered statistically significant. Microsoft Excel was used for statistical calculations.
III. Results and Discussion
1. BVC enhances PPARγ activity and adipogenesis
Given prior reports that bavachinin (BVC) functions as a PPARγ agonist, we first re-examined this activity under our experimental conditions to evaluate its potential strengths and limitations as a natural PPARγ modulator. To do this, we performed a reporter gene assay and PPARγ activity was examined on human embryonic kidney 293 (HEK293) cells. HEK293 cells were co-transfected with a PPREx3-tkluciferase reporter plasmid and mouse PPARγ expression vector. We used rosiglitazone (3 μM), a synthetic PPARγ ligand, as a positive control. As expected, rosiglitazone markedly increased PPARγ activity. BVC increased transcriptional activity of PPARγ in a dose-dependent manner <Figure 1B>. The increase in PPARγ activity of BVC was significant but lower than that of same dose of rosiglitazone. To further determine the transcriptional activation of PPARγ by BVC, we analyzed the mRNA expression of aP2, target gene of PPARγ, in response to BVC treatment in 3T3-L1 adipocytes. Consistent with the results of reporter gene assay, BVC also enhanced the expression of aP2 <Figure 1C>.
Next, we verified whether BVC is a ligand of PPARγ. To assess the interaction between BVC and PPARγ, the LanthaScreen TR-FRET competitive binding assay was performed. BVC had a half-maximum inhibitory concentration (IC50) value of 6.39 μM (Ki 2.29 μM) to PPARγ ligandbinding domain (LBD). Compared to rosiglitazone, the binding affinity of BVC to PPARγ LBD was moderate <Figure 1D>. Together with the PPARγ activity assay, these results indicate that BVC is a possible ligand of PPARγ and acts as a PPARγ agonist.
PPARγ is a well-known regulator of adipocyte differentiation (Tontonoz et al. 1994a). The agonistic ligands of PPARγ stimulate the differentiation of pre-adipocytes into mature adipocytes (Tontonoz et al. 1994b). Several reports indicate that BVC regulates adipocyte differentiation as a PPARγ agonist (Feng et al. 2016). Given these findings, we next examined whether BVC promotes the differentiation of hMSCs into mature adipocytes. Differentiation of hMSCs was executed with AIM in the presence of BVC or rosiglitazone during adipogenic differentiation. At 8 days after the initiation of differentiation, treatment with BVC increased adipocyte differentiation in a dose-dependent manner. Quantitative analysis following Oil Red O extraction confirmed this adipogenic effect of BVC <Figure 1E>, and the enhancement saturated at a BVC concentration of 3 μM. The expression of adipocyte differentiation markers was also increased by treatment with BVC. BVC augmented the level of PPARG, CEBPA, and fatty acid binding protein 4 (FABP4) compared with AIM only condition <Figure 1F, 1G>. These results suggest that BVC possesses mild adipogenic activity and are consistent with previous in vitro studies demonstrating that BVC promotes adipogenesis, supporting its role as a regulator of adipocyte differentiation. However, its effects in vivo have remained unclear.
To evaluate whether BVC also promotes adipogenesis in vivo, we implanted 3T3-F442A cells into nude mice to establish a de novo fat pad formation model. Although no significant difference was observed in the weight of the newly formed fat pads, treatment with BVC (5 mg/kg/day for 2 weeks) increased adipocyte size and density <Figure 1H>. The increased adipocyte density and size within de novo fat pads suggest that BVC facilitates adipose tissue expansion in vivo, which is in line with previous in vitro observations that BVC promotes adipocyte differentiation as a PPARγ agonist. The ability of BVC to facilitate adipose tissue expansion may, on the one hand, help buffer lipotoxic lipid spillover by increasing lipid storage capacity and reducing ectopic lipid deposition, but on the other hand, it raises the possibility that chronic exposure could exacerbate adipose tissue expansion and lead to PPARγ-related side effects including fluid retention, cardiac dysfunction and bone impairment.
2. BVC alleviates metabolic disorders in HFD-induced obese without fluid retention and cardiac dysfunction
Having established the adipogenic effects of BVC in vitro and in vivo, we next examined whether BVC also influences systemic metabolic parameters in diet-induced obese mice. Previous studies have shown that activation of PPARγ improves metabolic disorders associated with obesity and type 2 diabetes, including hyperglycemia and insulin resistance (Gadelha et al. 2014). Because BVC acts as a PPARγ agonist, we sought to evaluate both its beneficial and adverse metabolic effects in vivo. To induce hyperglycemia and insulin resistance, mice were fed a high-fat diet (HFD) for 4 weeks and were subsequently administered BVC (5 mg/kg/ day, i.p.) or vehicle for an additional 4 weeks.
To determine whether BVC could ameliorate glucose tolerance and insulin sensitivity, glucose tolerance tests (GTT) and insulin tolerance tests (ITT) were performed. In the GTT, intraperitoneal administration of 1 g/kg glucose demonstrated that BVC treatment significantly enhanced glucose tolerance compared with vehicle control <Figure 2A>. Fasting serum glucose levels exhibited a nonsignificant trend toward reduction in the BVC-treated group <Figure 2B> without body weight changes <Figure 2C>. In the ITT, BVC induced a significantly more sustained insulin response compared with vehicle-treated controls <Figure 2D>.
Furthermore, obesity-associated dysregulated gene sets in adipose tissue were restored by BVC treatment <Figure 2E>. Notably, the expression of 11 out of the 16 genes known to be dysregulated by phosphorylation of PPARγ at Ser273 (Choi et al. 2010) was restored in BVC-treated mice compared with vehicle controls. These anti-diabetic findings prompted us to examine whether BVC inhibits the phosphorylation of PPARγ at Ser273. To determine the effect of BVC on PPARγ phosphorylation, HEK293 cells were transfected with PPARγ, and phosphorylation was induced by treatment with PMA. BVC blocked PMA-induced phosphorylation in a dose-dependent manner <Figure 2F>, and the extent of inhibition was comparable to that of rosiglitazone. These results indicate that modulation of PPARγ phosphorylation at Ser273 contributes to the antidiabetic effects of BVC.
Some agonists of PPARγ, such as TZDs, cause side effects including weight gain, fluid retention, and heart failure. Increased renal sodium and water reabsorption induced by TZDs is associated with fluid retention and heart failure. Moreover, TZDs directly contribute to cardiac hypertrophy and heart failure through fetal gene reprogramming, including re-expression of natriuretic peptides and contractile protein switching (Nesto et al. 2004;Song et al. 2004;Lago et al. 2007). Therefore, we examined whether BVC-treated mice exhibited similar side effects. The body weight of BVC-treated mice was comparable to that of vehicle-treated controls <Figure 2A>. In addition, BVC did not induce hemodilution <Figure 2G> or cardiac hypertrophy <Figure 2H>. The transcript levels of skeletal muscle actin (Acta1), natriuretic peptide type A (Nppa), and natriuretic peptide type B (Nppb) in the heart were unchanged by BVC treatment, whereas β-myosin heavy chain (β-Myhc) expression was reduced <Figure 2I>. Renal expression of epithelial Na⁺ channels (ENaCs) in BVC-treated mice was also similar to that in control mice <Figure 2J>. These results support the notion that BVC exerts anti-diabetic effects without inducing TZD-like side effects such as fluid retention or cardiac dysfunction.
Taken together, these findings suggest that BVC functions as a selective PPARγ modulator that confers metabolic benefits without inducing the typical adverse effects associated with full agonists of PPARγ such as TZDs. The improvement in glucose tolerance and insulin sensitivity, along with the restoration of Ser273-dependent gene dysregulation, supports the notion that BVC exerts beneficial effects through PPARγ signaling. Notably, BVC did not cause fluid retention, cardiac hypertrophy, or ENaC upregulation, indicating that the adverse pathways commonly activated by TZDs are not triggered by BVC. This dissociation between metabolic efficacy and PPARγ-related side effects highlights the therapeutic potential of BVC as a safer PPARγ-targeting compound.
3. BVC ameliorates inflammation
PPARγ has been suggested to exert anti-inflammatory effects by suppressing the expression of pro-inflammatory genes and inducing anti-inflammatory genes across various tissues (Ricote et al. 1998;Chinetti et al. 2000). PPARγ agonists are also known to ameliorate inflammatory responses in both adipocytes and macrophages (Jiang et al. 1998). Therefore, we examined whether BVC similarly suppresses inflammatory responses in these cell types. In 3T3-L1 adipocytes, TNF-α stimulation markedly increased the expression of pro-inflammatory cytokines such as interleukin-1β (IL-1β), IL-6, and monocyte chemoattractant protein-1 (MCP-1), whereas pre-incubation with BVC suppressed this TNF-α-induced cytokine expression <Figure 3A>. In RAW 264.7 macrophages, BVC exhibited a similar inhibitory effect on lipopolysaccharide (LPS)-induced inflammatory responses <Figure 3B>. LPS robustly increased IL-1β, IL-6, MCP-1, and TNF-α expression, and these increases were significantly attenuated by BVC pretreatment. Nitric oxide (NO), a key mediator of macrophage-driven inflammation (Nathan and Hibbs 1991;Lee et al. 2024), has been implicated in the pathogenesis of chronic inflammatory diseases (Nagy et al. 2007). Consistent with previous results, NO production was reduced in a dose-dependent manner by BVC in LPS-stimulated RAW 264.7 cells <Figure 3C>.
Next, we investigated whether BVC exerts antiinflammatory effects in adipose tissue in vivo. HFD feeding induces chronic low-grade inflammation characterized by elevated pro-inflammatory cytokines (Lee 2024). Accompanied by increased lipid content, adipocytes secrete pro-inflammatory cytokines including TNF-α and IL-1β, IL-6, and chemotactic cytokines such as MCP-1 (Anghel and Wahli 2007). Consistent with the in vitro experiment with adipocyte and macrophage cells, BVC administration to HFD-fed mice significantly suppressed the expression of IL-1β, IL-6, and MCP-1 in adipose tissue, whereas TNF-α levels remained comparable to vehicle-treated controls <Figure 3D>. Antiinflammatory markers such as IL-10 and arginase showed a trend toward increased expression following BVC treatment, although the differences were not statistically significant <Figure 3E>.
Given previous evidence that enhanced lipolysis promotes adipose inflammation (Wang et al. 2009;Horrillo et al. 2010), we also examined the expression of lipolysisassociated genes. BVC-treated HFD-fed mice exhibited expression levels of hormone-sensitive lipase (HSL) and monoacylglycerol lipase (MGL) similar to those of controls, whereas adipose triglyceride lipase (ATGL) expression was reduced <Figure 3F>.
Collectively, these results indicate that BVC possesses potent anti-inflammatory activity in adipocytes, macrophages, and adipose tissue, likely through suppressing proinflammatory cytokine expression and attenuating lipolysisassociated inflammatory signaling. These anti-inflammatory actions may contribute to the improvement in insulin sensitivity observed in BVC-treated obese mice.
4. BVC inhibits osteoblast differentiation and bone regeneration
BVC exhibited several beneficial metabolic effects through PPARγ modulation. However, increased adipogenesis is typically associated with reduced osteogenesis due to the reciprocal relationship within the mesenchymal lineage. Thus, the impact of BVC on osteogenesis and bone homeostasis warrants careful evaluation. To assess the effects of BVC on osteogenesis, we examined its influence on osteoblast differentiation in hMSCs. hMSCs were induced toward osteoblasts using OIM, and cells were treated with BVC throughout the differentiation process. After 21 days of osteogenic differentiation, treatment with BVC suppressed osteoblast differentiation in a dose-dependent manner. Quantification of Alizarin Red S staining confirmed the inhibitory effect of BVC on mineralization <Figure 4A>. The expression of osteogenic marker genes, such as ALP and BMP2, was also decreased by BVC treatment <Figure 4B>.
To further determine the effect of BVC on bone formation in vivo, we created 4-mm calvarial defects in rats and applied collagen membranes saturated with BVC (100 μg) or vehicle onto the defect sites. Five weeks after surgery, vehicletreated membranes showed partial closure of the bony defects, whereas BVC-treated membranes exhibited minimal bone regeneration <Figure 4C>. Quantitative analysis of bone volume (BV) demonstrated that newly formed BV relative to the total defect volume (TV) was significantly lower in the BVC-treated defects (9.18%) compared with vehicle-treated controls (12.67%) <Figure 4D>. These results strongly indicate that BVC suppresses osteogenesis and impairs bone healing in vivo. The inhibitory effects of BVC on bone regeneration further support the notion that BVC negatively regulates osteoblast-mediated bone formation and acts directly on osteoblast lineage cells rather than through systemic metabolic changes. It suggests that BVC activates PPARγ-dependent transcriptional mechanisms that divert progenitor cell fate toward adipogenesis, thereby diminishing osteogenic potential.
Taken together with its adipogenic activity, the inhibitory effect of BVC on osteogenesis suggests that BVC biases mesenchymal lineage allocation toward adipogenesis at the expense of osteoblast differentiation. This lineage shift is consistent with the reciprocal relationship between adipogenic and osteogenic programs within the mesenchymal stem cell compartment. Notably, this phenotype mirrors the wellestablished skeletal side effects of TZDs, which promote adipogenic commitment of mesenchymal progenitors while suppressing osteoblast differentiation and bone formation. Although BVC exhibits milder PPARγ agonism compared with TZDs, our findings demonstrate that even partial activation of PPARγ by BVC is sufficient to suppress osteogenic programs in hMSCs and impair bone regeneration in vivo.
IV. Summary and Conclusion
In this study, we comprehensively evaluated the metabolic, inflammatory, and skeletal effects of BVC, a prenylated flavonoid from Psoralea corylifolia seeds, with a particular focus on its role as a natural PPARγ modulator. BVC moderately activated PPARγ, enhanced transcription of PPARγ target gene, and promoted adipogenic differentiation in vitro and in vivo. In diet-induced obese mice, BVC improved glucose tolerance and insulin sensitivity, restored Ser273-dependent transcriptional dysregulation, and inhibited PPARγ phosphorylation at Ser273. Importantly, BVC did not induce TZD-like adverse effects such as fluid retention, cardiac hypertrophy, fetal gene reprogramming, or ENaC upregulation, demonstrating a dissociation between metabolic efficacy and classical PPARγ-mediated side effects.
In addition, BVC exhibited potent anti-inflammatory effects in adipocytes, macrophages, and adipose tissue, suggesting that its metabolic benefits are further supported by attenuation of obesity-associated inflammation. However, BVC suppressed osteoblast differentiation of hMSCs, reduced expression of osteogenic markers, and impaired bone regeneration in a rat calvarial defect model. Taken together with its adipogenic activity, these findings indicate that BVC biases mesenchymal lineage allocation toward adipogenesis at the expense of osteoblast differentiation. This lineage shift parallels the skeletal defects observed with TZD, although BVC acts as a milder agonist. Our results demonstrate that even partial activation of PPARγ by BVC is sufficient to negatively regulate osteogenic programs and compromise bone healing.
Bone homeostasis is maintained through the coordinated activities of both osteoblasts and osteoclasts, and alterations in either lineage can affect bone regeneration and remodeling. In this context, it is noteworthy that a previous study reported that BVC alleviates osteoclast differentiation in RANKLinduced RAW 264.7 cells, suggesting a potential inhibitory effect of BVC on osteoclastogenesis (Liu et al. 2023). Based on this report, the impaired bone regeneration observed in the present study is more likely attributable to the direct suppression of osteoblast differentiation rather than enhanced osteoclast activity.
However, the effects of BVC on osteogenic differentiation appear to be context-dependent. Previous studies using murine cell lines, including MC3T3-E1 osteoblasts and C3H10T1/2 mesenchymal progenitors, reported that BVC promoted osteogenic differentiation (Liu et al. 2023), indicating potential species- and cell type-specific differences in BVC responsiveness. These discrepancies highlight the importance of experimental context, particularly differences between human and mouse cells, as well as between immortalized cell lines and primary stem cell populations. Therefore, further studies are warranted to elucidate the effects of BVC on human osteoclast differentiation and activity, as well as to comprehensively evaluate its impact on bone homeostasis using diverse in vivo models of bone regeneration and remodeling. Such investigations will be essential to clarify the mechanisms underlying the skeletal effects of BVC observed in this study.
Several previous studies have reported that BVC functions as a ligand of PPARγ, demonstrating that its biological effects are abolished or attenuated by the PPARγ antagonists T0070907 and GW9662, thereby supporting a PPARγ- dependent mechanism of BVC (Ge et al. 2019). Consistent with these findings, the present study further supports the PPARγ agonistic activity of BVC using stem cell-based differentiation models and in vivo animal experiments, providing functional evidence that BVC modulates metabolic, inflammatory, and skeletal phenotypes in a manner characteristic of PPARγ activation.
However, a limitation of the current study is that we did not directly confirm PPARγ as the exclusive molecular target of BVC using genetic approaches such as siRNA-mediated knockdown or conditional deletion of PPARγ. Although pharmacological and transcriptional evidence supports PPARγ involvement, future studies employing genetic lossof- function strategies will be required to definitively establish the extent to which the observed effects of BVC are strictly PPARγ-dependent.
Importantly, accumulating evidence indicates that BVC exerts pleiotropic biological activities through multiple signaling pathways beyond PPARγ. Previous reports have shown that BVC modulates the AKT/mTOR and MAPK/ ERK pathways, as well as ATM/ATR signaling, contributing to its anti-cancer (Hung et al. 2021) and cholesterol synthesis-inhibitory effects (Dong et al. 2020). In addition, BVC has been reported to inhibit monoamine oxidase activity, conferring antidepressant-like effects (Gohari et al. 2025), and to suppress HIF-1α signaling, thereby exhibiting anti-angiogenic properties (Nepal et al. 2012). These findings collectively suggest that BVC may act on multiple molecular targets in a context-dependent manner.
Therefore, it remains to be determined whether the effects of BVC on mesenchymal stem cell lineage allocation, osteoblast differentiation, and bone regeneration observed in this study are mediated exclusively through PPARγ activation or are partially influenced by PPARγ-independent pathways. Further investigation into the tissue-specific and pathwayselective actions of BVC will be essential to fully elucidate its mechanism of action and to assess its therapeutic potential and safety.
In conclusion, BVC acts as a selective PPARγ modulator that confers significant metabolic and anti-inflammatory benefits while simultaneously exerting adverse skeletal effects. These findings highlight the necessity of evaluating both therapeutic efficacy and skeletal risks when assessing natural PPARγ ligands derived from herbal or food-based ingredients, including BVC. Future studies should investigate the tissue-specific actions of BVC and explore the feasibility of developing BVC analogs or formulations that retain metabolic advantages while minimizing bone-related liabilities.
