A review of pharmacological properties and pharmacokinetic of 20(S)-protopanaxadiol

Ziliang He: Conceptualization, Investigation, Analysis, Writing–original draft. Yeye Hu: Investigation, Writing-original draft. Yuhao Wang: Investigation, Analysis, Literature search. Canglang Mou: Investigation, Literature search. Jae Youl Cho: Conceptualization, Writing–review & editing, Supervision, Funding acquisition. Long You: Conceptualization, Supervision.

In conclusion, PPD has emerged as a various and pharmacologically potent natural aglycone derived from Panax ginseng . Many studies have demonstrated its therapeutic potential in multiple diseases, including tumor, neurological diseases, metabolic dysfunction, immune regulation, and tissue repair. Acting as a multi-target regulatory molecule, PPD modulates several signaling pathways, such as AMPK/mTOR, NF-κB, and TGF-β/Smad, and others, thereby regulating diverse cellular activities such as programmed cell death, autophagy, oxidative stress, EMT, and ECM remodeling. These activities and mechanisms are summarized in Table 1 . Table 1 Pharmacological activities and molecular mechanisms of PPD. Table 1 Pharmacological Activities Effective Doses Models ( In vitro / In vivo ) Key Mechanisms Ref. Anti-breast cancer In vitro : 5-60 μM MCF-7, MDA-MB-231, SUM159, 4T1 ER antagonism; mitochondrial apoptosis induction; PI3K/AKT/mTOR and EGFR/MAPK pathways inhibition; suppression of EMT and metastasis; remodeling of tumor microenvironment [ [14] , [15] , [16] , [17] , [18] ] In vivo : 2.5-10 mg/kg MCF-7 or MDA-MB-231 xenograft nude mice, 4T1-bearing mice Anti-glioma In vitro : 32.5-108.4 μM SF188, U87MG, U251MG Apoptosis and cell death induction; autophagy activation and oxidative stress generation; cell cycle arrest via ERK pathway inhibition; migration and invasion suppression [ 19 , 20 ] - - Anti-liver cancer In vitro : 10-80 μM HepG2 and PLC/PRF/5 Apoptosis via ER stress induction and membrane remodeling; PI3K/AKT pathway inhibition; EMT suppression via STAT3 inhibition [ [21] , [22] , [23] , [24] , [25] , [26] ] In vivo : 20-100 mg/kg H22-bearing mice, PLC/PRF/5 xenograft mice Anti-prostate cancer In vitro : 10-45 μM LNCaP and C4-2 cells AR signaling inhibition via AR/AR-Vs degradation; AR transcriptional suppression via AF-2 binding; apoptosis induction and cell cycle arrest via VDR upregulation [ [27] , [28] , [29] , [30] , [31] ] In vivo : 70-100 mg/kg C4-2 or LNCaP xenograft mice Anti-colorectal cancer In vitro : 1-50 μM HCT-116 SW620, SW480 Apoptosis and paraptosis induction; Wnt/β-catenin and ERK pathways inhibition; JNK/p38 MAPK pathways activation; lipid activation via ER stress and p53 activation; RBBP4/PRC2 signaling inhibition; metastasis suppression via RXRα/β-catenin pathway inhibition; 5-FU sensitization [ [32] , [33] , [34] , [35] , [36] , [37] , [38] ] In vivo : 25-50 mg/kg CRC xenograft or lung metastasis mice Anti-lung cancer In vitro : 0.25-56 μM A549, H460, NCI-H1299 EGFR/MAPK pathway inhibition; cell cycle arrest and apoptosis induction via PI3K/AKT pathway inhibition; EMT suppression via SIRT1 inhibition; CTX chemosensitization [ [39] , [40] , [41] , [42] ] - A549 xenograft mice, Ang II–A549 metastasis mice Anti-endometrial cancer In vitro : 2.5-40 μM Ishikawa, RL95-2, HEC-1A Apoptosis via ERα signaling inhibition; autophagy activation; metformin synergistic effect [ 43 , 44 ] In vivo : 20 mg/kg HEC-1A xenograft mice Anti-laryngeal carcinoma In vitro : 40 μM Hep-2 Radio sensitization enhancement via mTOR pathway inhibition; cell cycle arrest and apoptosis induction [ [45] , [46] , [47] , [48] ] In vivo : 20 mg/kg Hep-2 xenograft mice Anti-gastric cancer In vitro : 9 μM HGC-27 Cell death induction via lysosomal dysfunction and mito-ROS [ 49 ] - - Anti-cervical cancer In vitro : 20-40 μM Hela Apoptosis induction via ER stress; cell death induction via mitochondrial dysfunction; EMT suppression via PI3K/AKT and MAPK pathways inhibition [ 50 , 51 ] - - Anti-acute myeloid leukemia In vitro : 20-60 μM MOLM-13, MV4-11, THP-1 PI3K/AKT/mTOR pathway inhibition; PERK-mediated ER stress activation; c-Myc destabilization; apoptosis promotion via MCL-1/Bcl-XL degradation [ 52 , 53 ] - - Anti-melanoma In vitro : 40-80 μM SK-MEL-28 Apoptosis induction via MLK3/JNK pathway activation [ 54 ] - - Neuroprotection In vitro : 10-40 μM NSCs NSCs differentiation, proliferation and migration via Wnt/GSK-3β/β-catenin pathway activation [ [63] , [64] , [65] ] - - Anti-depression and stress In vitro : 10-100 μM Mouse brain SNs and SS, HT-22 HPA axis normalization and monoamine restoration; BDNF/TrkB/CREB activation via 14-3-3ζ/GSK-3β regulation; SIRT1/PGC-1α pathway activation; GABA modulation via sodium channel inhibition; CK-BB activation; Dyn A release via GR activation [ [66] , [67] , [68] , [69] , [70] , [71] , [72] , [73] , [74] , [75] ] In vivo : 5-80 mg/kg CMS mice, OB rats, CSDS mice, CORT-treated mice. CUMS rats, immobilization stress mice Cognitive protection In vitro : 10 μM PC12 Neurogenesis via Wnt/GSK-3β activation; antioxidant via mitochondrial protection; cholinergic restoration via AChE inhibition; NLRP3 inflammasome suppression; PURA activation; CK-BB activation [ [76] , [77] , [78] , [79] , [80] , [81] ] In vivo : 9-20 mg/kg APP/PS1 transgenic mice, SCOP-treated mice, VD rats Vascular regulation In vitro : 20-120 μM Aortic smooth muscle VDCCs block; renin–angiotensin suppression via ACE inhibition; ROS scavenging [ 84 , 85 ] - - Cardiovascular protection In vitro : 21.7 μM EAhy 926 LDLR/PCSK9 activation; of apoptosis inhibition; oxidative stress suppression [ [86] , [87] , [88] ] In vivo : 20-60 mg/kg HFD-ApoE −/− mice, myocardial I/R rats Anti-angiogenesis In vitro : 1-50 μM HUVECs GR activation; ER stress apoptosis induction via PERK/eIF2α/ATF4/CHOP activation [ 89 , 90 ] - - Hemostasis In vitro : 10-40 μM Human platelets PAR-1 activation; Ca 2+ influx; PI3K/Akt/p38 MAPK pathways activation [ 91 ] In vivo : 2-8 mg/kg mouse tail amputation model, liver scratch model Anti-photoaging In vitro : 1-10 μM HaCaT; reconstructed human skin model ROS scavenging; MEK/ERK/p38 MAPK pathways inhibition; MMPs suppression [ 93 ] - - Wound Healing In vitro : 2.5-12.5 μM HUVECs PI3K/Akt/mTOR and Raf/MEK/ERK pathways activation; p70S6K/HIF-1α/VEGF activation; macrophage M2 polarization [ [94] , [95] , [96] , [97] ] In vivo : 1.3 × 10 5  μM Full-thickness excisional wound model, STZ-induced diabetic wound model Anti-alopecia In vitro : 10 μM DPCs, HUVECs Wnt/β-catenin pathway activation; inflammation inhibition [ 98 ] 1 mg/mice AGA mice Anti-obesity In vitro : 30 μM HCT116 Appetite suppression via PVH neuronal activation; GCN2/PERK/Sesn2/AMPK activation [ 99 , 100 ] In vivo : 2.5-100 mg/kg HFD mice Lipid metabolism In vitro : 5-500 μM C2C12, HepG2, 3T3-L1 Enrichment of A. muciniphila ; FXR/CYP7A1 pathway activation; oxidative stress suppression [ [101] , [102] , [103] ] In vivo : 60 mg/kg HFD mice Insulin regulation In vitro : 5-25 μM HepG2, INS-1, C2C12, 3T3-L1 AMPK and PI3K/AKT pathways activation; FoxO1 inhibition; PDX-1 restoration [ 103 , 104 ] - - Anti-renal fibrosis 5-21.7 Primary rat glomerular mesangial cells, HK-2 TGF-β/Smad, MAPK and PI3K/AKT pathways inhibition [ 105 , 106 ] 20 mg/kg db/db mice AKI protection In vitro : 10-40 μM HK-2 Ferroptosis inhibition; GPX4/FSP1 pathway activation [ 107 ] In vivo : 20-80 mg/kg CDDP-induced AKI mice Immune nephropathy protection - - PTX3/MAPK/ERK pathway inhibition; GR regulation [ 108 , 109 ] In vivo : 30-90 mg/kg MRL/lpr mice, ALB-treated rats Anti-hepatic fibrosis In vitro : 1-20 μM LX2, primary HSCs, HepG2 TGF-β/Smad pathway suppression via TGFβR1 inhibition; Wnt/β-catenin pathway suppression via DNMT1 inhibition; AMPK/SIRT1 pathway activation; LKB1/AMPK/mTOR pathway activation [ [110] , [111] , [112] , [113] ] In vivo : 10-20 mg/kg HFD mice, CCl 4 fibrosis model Anti-pulmonary fibrosis In vitro : 2 μM MLE-12 AMPK/STING pathway activation through gut–lung axis; NF-κB and TGF-β/Smad pathway inhibition; SPHK1/S1P/mTOR inhibition [ 11 , 114 ] In vivo : 10-40 mg/kg BLM-treated mice Anti-osteolysis In vitro : 1.25-2.5 μM BMDMs, Raw 264.7 MAPK/NF-κB pathways suppression via TAK1 inhibition [ 115 ] In vivo : 2-5 mg/kg Ti-particle-treated mice Anti-periodontitis 47.8 μM RAW 264.7, L929, HGFs ROS scavenging; macrophage M2 polarization [ 116 ] 4.4 μg/mice P. gingivalis -treated rats Endometriosis protection In vitro : 40 μM eESCs, NK cells PR upregulation via ERα downregulation; autophagy activation; NK cells activation [ 117 , 118 ] In vivo : 20-45 mg/kg Endometriosis mice Immune Regulation In vitro : 10-20 μM HeLa, HepG2, HEK293 NF-κB inhibition via GR transrepression; NK cells activation; gut–bone marrow axis modulation [ 129 , 130 ] In vivo : 50 mg/kg CTX-treated mice Retinopathy protection In vitro : 2 μM ARPE-19 Autophagy restoration via AMPK/mTOR pathway activation; apoptosis inhibition via ROS scavenging [ 131 ] - - Anti-aging - - Activation of DAF-2/insulin/IR axis and DAF-16/FOXO [ 134 ] In vivo : 100-400 μM C. elegans Pharmacological activities and molecular mechanisms of PPD. Despite these various pharmacological activities, the clinical translation of PPD remains confined by several pharmacokinetic limitations. Its lipophilicity, relatively low oral bioavailability, and Phase I hepatic metabolism may restrict systemic exposure and therapeutic efficacy. Fortunately, the development of delivery technologies, including nanostructured lipid carriers, cholesterol-free liposomes, and TPGS-stabilized nanocrystals, has shown significant potential in improving solubility, absorption, and targeted tissue delivery of PPD. In future research, some key problems require further research to realize the therapeutic potential of PPD. First, notable species differences in metabolism suggest the necessity for more clinical metabolic studies. Second, inconsistent findings regarding the inhibitory effects of PPD on major cytochrome P450 enzymes (CYP3A4 and CYP2B6), require systematic evaluation to accurately assess potential drug–drug interaction risks during combination therapy. AS these challenges are gradually resolved, PPD is expected to demonstrate even greater therapeutic potential.

Panax ginseng Meyer has been widely used in traditional medicine for centuries and is recognized for its various therapeutic properties. As the traditional medicinal herb, ginseng has demonstrated broad therapeutic effects in various diseases, including cancer, skin damage, neurological disease, diabetes and inflammation [ [1] , [2] , [3] , [4] , [5] ]. The important bioactive components responsible for these effects are ginsenosides, including triterpenoid saponins, including protopanaxadiol-type (PPD-type) saponins, protopanaxatriol-type (PPT-type) saponins, and oleanane-type ginsenosides. Following oral administration, ginsenosides are metabolized into active aglycone metabolites by intestinal microbiota [ 6 ]. Among these metabolites, PPT-type saponins are metabolized into GF1, Rh1, Re, F1, and ultimately converted into 20(S)-protopanaxatriol (PPT). PPD-type saponins are metabolized into more bioactive metabolites, including Rd, CO, Rb2, Rh2, GF2, Md, Mc and CK, and ultimately converted into 20(S)-protopanaxadiol (PPD) [ 7 ]. Over the past decade, accumulating evidence has shown PPD as a promising pharmacological natural compound with broad therapeutic potential. Extensive experimental studies have demonstrated its various protective effects in vitro and in vivo , including anti-tumor, anti-inflammatory, neuroprotective, and anti-fibrotic effects [ [8] , [9] , [10] , [11] ]. Beyond its pharmacological activities, the pharmacokinetic characteristics of PPD have also attracted more attention. Due to its highly lipophilic structure, PPD exhibits moderate oral bioavailability and undergoes hepatic metabolism in vivo , followed by broad distribution across various organs and tissues [ 12 , 13 ]. This is the basis of its various pharmacological effects. Despite increasing research on PPD, a comprehensive and systematic summarization of its pharmacological activities, molecular mechanisms, and pharmacokinetic characteristics remain lacking. Therefore, this review aims to provide an updated and comprehensive overview of the pharmacologic and pharmacokinetic of PPD.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ginseng exhibited strong anti-cancer effects [ 5 ]. Among the bioactivity compounds in ginseng, PPD demonstrates the potential of anti-cancer. Extensive studies have shown that PPD suppresses tumor progression through multiple mechanisms, including the inhibition of tumor cell proliferation, the induction of programmed cell death, and the suppression of tumor metastasis and epithelial–mesenchymal transition (EMT). PPD demonstrates significant anti-breast cancer activity through estrogen receptor-dependent or estrogen receptor-independent mechanisms in vitro and in vivo . In MCF-7 cells (estrogen receptor-positive breast cancer cells), PPD effectively inhibited 17β-estradiol (E2)-induced cell proliferation by blocking estrogen receptor. In addition, PPD showed a strong synergistic effect when combined with tamoxifen, leading to significant tumor growth inhibition in the MCF-7 xenograft mouse model [ 14 ]. Beyond estrogen receptor blocking, in MCF-7 cells, PPD disrupted mitochondrial membrane potential (MMP), regulated the Bcl-2/Bax expression ratio, and activated the caspase-9/caspase-3 cascade, resulting in cell apoptosis [ 15 ]. Further studies showed that this mitochondrial apoptosis was induced by inhibiting PI3K/AKT/mTOR signaling pathway and its downstream target 4EBP1. The involvement of this pathway was supported by PI3K inhibitor (LY294002) enhancing this apoptosis induced by PPD. These findings suggest that PPD play the anti-breast cancer role by inhibiting cell growth and inducing apoptosis. On the other hand, PPD also exhibits activity in estrogen receptor-negative breast cancer cells, such as MDA-MB-231 and SUM159 cells. In vivo , daily intraperitoneal administration of PPD significantly suppressed orthotopic tumor growth and lung metastasis in xenograft models. Mechanistic studies indicated that PPD inhibited metastasis by inhibiting EGFR/MAPK signaling pathway. In addition, researchers found that PPD could inhibit cell invasion through the EMT reversion and the regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) [ 16 ]. Besides, PPD exhibited a stronger anti-cancer activity through combination with other drugs and advanced delivery systems. Fu et al. developed a lipid nanoparticle system for the co-delivery of PPD and cannabidiol (CBD). This strategy produced strong synergistic antitumor effects, achieving 82.6% inhibition of breast tumor growth while reducing the toxicity associated with CBD treatment. This strong effect was mainly attributed to the excessive generation of reactive oxygen species (ROS) [ 17 ]. In another study, Yu et al. explored a liposome-based drug delivery system loaded with PPD, paclitaxel and PD-L1 antibodies, in which PPD as a functional structural component. This system induced strong apoptosis and effectively suppressed TNBC progression in vivo , showing greater effect than free paclitaxel or conventional liposomes. Importantly, in this system, PPD remodeled the tumor microenvironment by reducing cancer-associated fibroblasts (CAFs) and promoting macrophage polarization from the M2 to the M1 phenotype [ 18 ]. In human glioma, PPD shows strong anti-glioma activity through multiple mechanisms, including the induction of programmed cell death, cell cycle arrest, and the inhibition of tumor cell motility. Interestingly, PPD induces cell death through different pathways depending on the glioma cell line. In SF188 cells, PPD induced caspase-dependent apoptosis, characterized by the activation of caspases-3, -7, -8, and -9. But in U87MG cells, PPD induced a caspase-independent cell death pathway. In addition, PPD promoted autophagy and increased oxidative stress in both cell lines. Notably, this cell death in SF188 cells could be completely blocked by the combination treatment of the caspase inhibitor and the antioxidant, indicating that PPD play the anti-glioma role through inducing apoptosis and ROS generation [ 19 ]. Besides, another research indicated that PPD also affected glioma by inhibiting cell proliferation and cell metastasis. In this research, PPD induced G0/G1 cell cycle arrest by downregulating Cyclin D1 and Cyclin E. And further studies indicated that this effect was induced by inhibiting the ERK signaling pathway. Moreover, PPD significantly inhibited cell migration and invasion by downregulating the expression of N-cadherin, integrin β1, focal adhesion kinase (FAK), and paxillin [ 20 ]. Together, these findings indicate that PPD exerts anti-glioma activity by inducing tumor cell death and suppressing cell proliferation and invasion. In hepatocellular carcinoma (HCC), PPD exhibits strong anti-tumor activity through multiple mechanisms, Zhu et al. reported that PPD induced endoplasmic reticulum (ER) stress in HepG2 cells by activating the unfolded protein response (UPR) through PERK, IRE1, and ATF6 sensors. This process significantly increased the expression of the pro-apoptotic transcription factor CHOP by activating ERK pathway, resulting in apoptosis induction [ 21 ]. Besides, PPD promotes mitochondrial apoptosis by suppressing PI3K/AKT signaling pathway [ 22 ]. In addition, Li et al. showed that combining PPD with intermittent fasting conditions (low glucose and low serum) significantly strengthened anti-HCC effect. In H22 tumor-bearing mice, this strategy significantly induced apoptosis, reduced metastasis and prolonged survival by inhibiting PI3K/AKT/mTOR pathway [ 23 ]. Beyond classical signaling pathways, PPD also can insert into the plasma membrane and form rigid membrane microdomains termed “PPD rafts”, due to its cholesterol-like structure. This process changes membrane tension and disrupts membrane tubulation, thereby sensitizing HCC cells to FasL-mediated extrinsic apoptosis [ 24 ]. Besides, in PLC/PRF/5 xenograft models, PPD significantly reduced primary tumor growth and lung metastasis. This anti-metastatic effect was associated with the reversal of EMT, as indicated by the high expression of E-cadherin and low expression of Vimentin and Twist1. Mechanistic studies further demonstrated that this effects of PPD were associated with STAT3 inhibition. Specifically, PPD directly binds to the SH2 domain of STAT3 (KD = 26.8 μM) through hydrogen bonds with Gly583, Leu608, and Tyr674, thereby inhibiting STAT3 activation and the expression of metastasis-related genes [ 25 ]. Moreover, Han et al. constructed a nanoparticle formulation (PPD-NPs) with a stronger anti-HCC effect. This system significantly increased oral bioavailability, thereby enhancing the anti-HCC effect of PPD in vitro and in vivo [ 26 ]. In human prostate cancer, PPD exhibited a strong anti-tumor effect through multiple mechanisms. Cao et al. reported that PPD significantly inhibited castration-resistant prostate cancer (CRPC) cells growth by promoting the degradation of full-length androgen receptor (AR-FL) and androgen receptor splice variants (ARR-Vs), which are major drivers of drug resistance [ 27 , 28 ]. And in the C4-2 xenograft model, oral administration of PPD suppressed tumor growth, which further confirmed the PPD's effect. In addition, in the LNCaP model, when PPD was administered immediately after castration, it significantly inhibited tumor regrowth and reduced the development of castration resistance [ 28 ]. Mechanistic studies showed that PPD directly interacts with the AR. Molecular docking analysis revealed that PPD selectively binds to the AF-2 pocket within the AR ligand-binding domain, which is different from the binding sites of conventional anti-androgens such as enzalutamide. Therefore, PPD can be combined with enzalutamide, resulting in synergistical inhibition of AR transcriptional activity. This combination significantly reduces serum prostate-specific antigen (PSA) levels and promoted apoptosis in prostate cancer models [ 29 ]. Furthermore, PPD also functions as a sensitizer in combination therapy. Calcitriols usually induce the upregulation of CYP24A1 expression resulting in calcitriol degradation. In this research, PPD could maintain higher intracellular levels of calcitriol by suppressing the CYP24A1 expression. Meantime, PPD increased the expression of the vitamin D receptor (VDR), which further enhanced downstream signaling. Therefore, combination treatment with PPD and calcitriol produced strong anti-proliferative effects in LNCaP and C4-2 cells [ 30 ]. Consistent with these in vitro findings, combination treatment with PPD and calcitriol resulted in approximately 76% inhibition of tumor growth in vivo . This anti-tumor effect was associated with apoptosis and cell cycle arrest, accompanied by the upregulation of p21 and p27 [ 31 ]. Together, these studies indicate that PPD exhibited a strong anti-tumor effect in prostate cancer through multiple pathways. In colorectal cancer (CRC), PPD exhibits anti-tumor activity through multiple mechanisms. Early studies showed that PPD induced membrane damage and apoptosis in intestinal cancer cell lines such as Caco-2 and Int-407 [ 32 ]. In HCT116 cells, PPD can induce paraptosis, a caspase-independent form of programmed cell death characterized by cytoplasmic vacuolization and mitochondrial swelling. And the research indicated that this effect was associated with activation of oxidative stress and NF-κB pathway [ 33 ]. Besides, PPD induced G0/G1 cell cycle arrest by inihibing Wnt/β-catenin and ERK pathways. Meantime, PPD also induced apoptosis by activating JNK and p38 MAPK pathways [ 34 ]. Another research indicated that PPD interfered with lipid metabolism, leading to lipid droplet accumulation, ER stress, and p53-mediated apoptosis [ 35 ]. These results show that PPD-induced apoptosis is associated with multiple pathways. Chemoproteomic analysis also revealed that PPD directly binds to RBBP4, disrupting the PRC2 complex and recovering the transcriptional repression induced by H3K27me3 [ 36 ]. And in several xenograft models, PPD suppressed tumor growth and metastasis by regulating the RXRα/β-catenin signaling pathway. Moreover, PPD enhanced the anti-tumor activity of 5-fluorouracil (5-FU), suggesting its potential as an adjuvant therapy in CRC treatment [ 37 , 38 ]. In lung cancer, PPD functions as both a direct anti-tumor agent and a chemosensitizing adjuvant. In Lewis lung carcinoma (LLC) models, PPD alone showed limited anti-tumor activity. But combination treatment with PPD and cyclophosphamide (CTX) exhibited a stronger anti-tumor effect. Importantly, PPD also protected the immune and hematopoietic systems from chemotherapy-induced toxicity, suggesting a potential role as an immunoprotected adjuvant during cancer treatment [ 39 ]. Regarding its direct anti-tumor role, in human non-small cell lung cancer (NSCLC) cells, PPD can induce cell cycle arrest at the G0/G1 phase by directly binding to epidermal growth factor receptor (EGFR), thereby inhibiting MAPK pathway [ 40 ]. At the same time, PPD induces mitochondrial apoptosis by suppressing PI3K/Akt/GSK-3β signaling pathway. This process involves MMP loss, the release of cytochrome c , Smac, and AIF, and subsequent caspase activation [ 41 ]. In metastatic mouse models, oral administration of PPD significantly reduced lung metastatic nodules. Mechanistic studies indicated that PPD inhibited angiotensin II-induced EMT by downregulating SIRT1 expression. As a result, mesenchymal transcription factors such as Snail, Slug, and ZEB1 are suppressed, while the epithelial marker E-cadherin is restored, thereby reducing tumor cell migration and invasion [ 42 ]. In endometrial cancer, PPD shows promising anti-tumor activity in both estrogen-sensitive and hormone-independent endometrial cancer. In estrogen-sensitive endometrial cancer cell lines, such as Ishikawa and RL95-2, PPD significantly suppressed estrogen-mediated cell proliferation by inhibiting estrogen receptor α (ERα) expression. This inhibition also induced apoptosis and autophagy. Notably, PPD exhibited a synergistic effect when combined with metformin, exhibiting a stronger anti-proliferative activity than either agent alone [ 43 ]. In hormone-independent endometrial cancer cell lines such as HEC-1A cells, PPD induced sub-G1 cell cycle arrest and activated the intrinsic mitochondrial apoptotic pathway. And the in HEC-1A xenograft models, PPD significantly suppressed tumor growth, which further confirmed the in vitro findings [ 44 ]. These research shows a strong anti-tumor effect of PPD in endometrial cancer. In human laryngeal carcinoma, PPD exhibits therapeutic potential both as a direct anti-tumor agent and as a radiosensitizer. Although ionizing radiation (IR) can inhibit Hep-2 cell proliferation, it often induces compensatory activation of the mTOR signaling pathway, which contributes to radioresistance. But Teng et al. indicated that pretreatment with PPD effectively suppressed IR-induced mTOR activation and downregulated its downstream targets, including eIF4E, 4EBP1, and HIF-1α, thereby enhancing the sensitivity of cancer cells to radiation therapy [ 45 ]. In addition to radiosensitization, PPD directly inhibits laryngeal cancer cell growth by inducing G2/M cell cycle arrest and apoptosis. Using direct stochastic optical reconstruction microscopy (dSTORM), Teng et al. further demonstrated that PPD reduced the expression and disrupted the spatial organization of the mTOR signaling complex [ 46 ]. Furthermore, several advanced delivery systems have been developed. PPD were encapsulated into PEG-modified hollow gold nanoparticles or electrospun polycaprolactone nanofibers. These two systems significantly enhanced drug delivery and tumor inhibition in both in vitro and in vivo [ 47 , 48 ]. In gastric cancer, PPD suppresses tumor cell survival through a distinct non-apoptotic mechanism. Han et al. reported that in HGC-27 gastric cancer cells, PPD induced lysosomal impairment together with excessive mitochondrial reactive oxygen species (mito-ROS) generation. Importantly, instead of activating a functional autophagic response, PPD blocked the late stage of autophagic flux by inhibiting the degradation phase. As a result, autophagic vacuoles accumulated within the cytoplasm, leading to cellular toxicity. Meantime, PPD caused significant mitochondrial damage, which promoted excessive ROS generation, which further disrupted lysosomal membrane. And the dysfunctional lysosomes cannot remove damaged mitochondria. This reciprocal amplification of mitochondrial and lysosomal damage formed a destructive intracellular loop that ultimately induced non-apoptotic programmed cell death [ 49 ]. In human cervical cancer, PPD shows significant anti-tumor activity. In HeLa cells, PPD significantly suppressed cell proliferation by inducing G0/G1 cell cycle arrest, followed by apoptosis. Mechanistically, PPD activated strong ER stress by stimulating the unfolded protein response (PERK, ATF6, and IRE1), resulting in the upregulation of CHOP. This ER stress response disrupted intracellular calcium balance and damaged mitochondrial function, ultimately inducing programmed cell death [ 50 ]. Beyond its anti-proliferation effect, multi-omics analysis indicated that PPD could reverse EMT. And in vitro experiments further confirmed that PPD significantly inhibited the migration and invasion of cervical cancer cells by inhibiting PI3K/AKT and MAPK signaling pathways [ 51 ]. Together, these findings suggest that PPD exhibits therapeutic potential for cervical cancer. In acute myeloid leukemia (AML), PPD shows strong anti-leukemic activity and functions as an effective agent for overcoming drug resistance. PPD directly inhibited the proliferation of AML cells and induced apoptosis. Mechanistically, PPD suppressed the PI3K/AKT/mTOR signaling pathway, activated PERK-mediated ER stress, and destabilized c-Myc, thereby inducting apoptosis [ 52 ]. In addition, PPD can destroy the drug resistance in AML cells. Venetoclax (ABT-199), a Bcl-2 inhibitor, is widely used in AML therapy. But it always induces the resistance in AML cells by increasing MCL-1 and Bcl-X L expression. Xu et al. found that PPD could promote the degradation of MCL-1 and Bcl-X L by directly binding to them, thereby restoring the apoptotic sensitivity. Therefore, the combination treatment with PPD and Venetoclax induced strong synergistic apoptosis and eliminated cytarabine-resistance in AML cells [ 53 ]. These findings indicate the potential of PPD as a promising adjuvant strategy for the treatment of AML. In human melanoma, PPD has exhibited the anti-tumor activity. He et al. found that PPD could significantly reduce the cell viability in various human melanoma cells. Network pharmacology analysis indicated that MAPK pathway is the key mechanism. Furthermore, in vitro experiments confirmed that PPD significantly activated the JNK MAPK pathway, rather than ERK or p38 MAPK pathway, by binding to and activating Mixed-Lineage Kinase 3 (MLK3), resulting in the induction of apoptosis. This research provides a new mechanism, that PPD can activate MLK3/JNK apoptotic axis promoting apoptosis [ 54 ]. Many studies have demonstrated that ginseng exhibited a strong neuroprotective effect [ [55] , [56] , [57] , [58] , [59] , [60] , [61] , [62] ]. And other studies pointed out that PPD might be the main bioactivity compound in ginseng of this effect. Chen et al. reported that PPD induced cell cycle arrest at the G0/G1 and G2/M phases, a process that prepared NSCs for subsequent differentiation. Meantime, the expression of the neuronal marker β3-tubulin was significantly increased, indicating a shift of NSCs toward neuronal lineage commitment. Mechanistic studies further revealed that this effect was mainly mediated through regulation of the Wnt/β-catenin pathway [ 63 ]. Another research demonstrated that PPD activated the Wnt/β-catenin signaling pathway by directly inhibiting GSK-3β. This activation promoted NSC proliferation and migration while preferentially directing their differentiation into mature neurons (MAP2 + ) rather than astrocytes [ 64 ]. Interesting, Wang et al. pointed that PPD-type ginsenosides exhibited stronger neuroprotective effect compared to PPT-type ginsenosides. PPT-type saponins could nullify the effect of PPD-type saponins [ 65 ]. These findings suggested the therapeutic potential of PPD in central nervous system (CNS). PPD exhibits anti-depressant effects in several stress-induced animal models through multiple mechanisms. Duan et al. found that PPD limited excessive neuronal depolarization and modulates γ-aminobutyric acid (GABA) release by inhibiting voltage-gated sodium channels, resulting in the anti-depressant effect [ 66 ]. In vivo studies indicated that chronic PPD administration effectively reversed depressive behaviors, including anhedonia and social avoidance, in chronic mild stress (CMS), olfactory bulbectomized (OB), and chronic social defeat stress (CSDS) models [ [67] , [68] , [69] ]. Notably, the aglycone form PPD displayed stronger antidepressant activity than its parent ginsenosides (e.g., Rb3). This may result from enhanced brain penetration and stronger receptor interactions [ 68 ]. Mechanistic studies revealed that PPD alleviated depressive symptoms by restoring neuroendocrine and neurotransmitter balance. It normalized the hyperactive hypothalamic–pituitary–adrenal (HPA) axis, reduced corticosterone levels, and restored key monoamine neurotransmitters, including serotonin (5-HT), dopamine (DA), and norepinephrine (NE) [ 67 , 68 , 70 ]. Meantime, PPD promoted neurotrophic signaling by activating the BDNF/TrkB/CREB pathway in the hippocampus and prefrontal cortex, which is essential for synaptic plasticity and emotional regulation [ 69 ]. Another study indicated that this activation was associated with interaction with PPD and 14-3-3ζ. PPD suppressed GSK-3β activity and subsequently promoted CREB activation by enhancing the interaction between 14-3-3ζ and GSK-3β [ 71 , 72 ]. In addition, PPD protected hippocampal neurons from stress-induced apoptosis and neuroinflammation by activating the SIRT1/NF-κB and SIRT1/PGC-1α pathways [ 70 , 73 ]. And PPD improved cerebral energy metabolism through direct activation of brain-type creatine kinase (CK-BB) [ 74 ]. Besides, PPD also alleviated chronic neuropathic pain by activating glucocorticoid receptors (GR) in spinal microglia, leading to the release of dynorphin A (Dyn A) and subsequent analgesic signaling [ 75 ]. Furthermore, Zhu et al. developed a nanoformulation strategy termed PEG-PCL nanomicelle-based Nano-PPD. This system prolonged systemic circulation and enhanced antidepressant effect in vivo through BDNF-mediated mechanisms [ 10 ]. PPD shows strong neuroprotective activity in models of Alzheimer's disease (AD), vascular dementia (VD), and aging-related cognitive decline. In transgenic APP/PS1 mice, PPD significantly improved learning and memory by promoting hippocampal neurogenesis through activation of the Wnt/GSK-3β signaling pathway [ 76 ]. PPD also protects neurons from toxic stress. In glutamate exposure and sleep deprivation models, PPD could suppress the oxidative stress by activating the expression of superoxide dismutase (SOD) and catalase (CAT), while preventing mitochondrial membrane damage [ 77 ]. In scopolamine (SCOP)-induced memory impairment, PPD rapidly restored cholinergic function by inhibiting acetylcholinesterase (AChE) and increasing the expression of memory-related genes such as c-Fos and Egr-1 [ 78 ]. Besides, PPD also exerted protective effects through directly regulating the neuroregulatory proteins. In VD models, PPD suppressed the activation of NLRP3 inflammasome, thereby reducing microglial pyroptosis and suppressing amyloid and Tau accumulation [ 79 ]. In aging-related cognitive decline, PPD increased the expression of genes involved in neuronal structure and myelin repair, including MBP and MAP2, by directly binding to PURA at Ser102 [ 80 ]. In addition, Zhang et al. indicated that PPD could stabilize CK-BB, which enhanced local ATP production and provided metabolic support for synaptic maintenance in the aging brain [ 81 ]. Collectively, these findings suggest PPD as a promising neuroprotective compound with multi-target mechanisms for preventing cognitive decline and neurodegeneration. Many studies demonstrated that ginseng exhibited cardiovascular and vascular regulative effects [ 82 , 83 ]. PPD exerts multiple beneficial effects on the cardiovascular system, including vascular regulation, cardiovascular protection, anti-angiogenesis activity, and hemostatic activity. PPD shows promising potential for the management of hypertension and vascular spasms. Gan et al. found that PPD produced a strong vasorelaxant effect in aortic smooth muscle that was largely independent with endothelium. And this study indicated that PPD functioned mainly as a calcium channel blocker by inhibiting the influx of extracellular Ca 2+ through L-type voltage-dependent calcium channels (VDCCs) and reducing Ca 2+ release from the sarcoplasmic reticulum, rather than acting through nitric oxide signaling, as observed for Rg3. This dual inhibition decreased intracellular calcium levels and promoted vascular smooth muscle relaxation [ 84 ]. In addition to its direct vasodilatory effect, PPD also acted as a mixed-type inhibitor of angiotensin-converting enzyme (ACE). The aglycone structure of PPD enabled stronger binding within the ACE catalytic pocket, including interaction with the catalytic Zn 2+ ion, thereby reducing angiotensin II production and suppressing hypertensive signaling. Moreover, PPD exhibited antioxidant activity by scavenging ROS, which may further contribute to its protective effects on vascular function [ 85 ]. PPD exerts protective effects on the cardiovascular system by reducing oxidative stress, improving lipid metabolism, and limiting ischemic injury. At the cellular level, PPD promoted endothelial repair and protected vascular cells from oxidative damage by increasing the expression of antioxidant enzymes, including heme oxygenase-1 (HO-1) and glutathione synthetase (GSS) [ 86 ]. In atherosclerosis models using ApoE knockout mice, PPD significantly lowered plasma cholesterol levels and reduced atherosclerotic plaque formation. This effect is mainly mediated through regulation of the LDLR/PCSK9 pathway. PPD enhanced the transcription of the low-density lipoprotein receptor (LDLR) while simultaneously inhibiting the interaction between PCSK9 and LDLR, thereby preventing LDLR degradation and improving cholesterol clearance [ 87 ]. In addition, PPD shows strong cardioprotective activity during myocardial ischemia/reperfusion (I/R) injury. In rat models, PPD pretreatment reduced infarct size and preserved cardiac function by enhancing antioxidant defense systems and suppressing mitochondrial apoptosis through inhibition of the Bax/caspase-3 pathway [ 88 ]. Collectively, these findings indicate that PPD protects the cardiovascular system through the regulation of oxidative stress, lipid metabolism, and cell survival pathways. PPD displays a dual regulatory effect on vascular endothelial cells. While it protects quiescent endothelial cells in normal vessels, it suppresses the abnormal endothelial proliferation required for tumor angiogenesis. In human umbilical vein endothelial cells (HUVECs), PPD exhibited strong anti-angiogenic activity and inhibited cell proliferation at low concentrations. Mechanistically, PPD suppressed endothelial cell proliferation by activating GR. This mechanism is different from other ginsenosides such as PPT [ 89 ]. In addition, PPD promoted apoptosis in proliferating endothelial cells by inducing ER stress. Specifically, it activated the PERK/eIF2α/ATF4/CHOP signaling pathway, which disrupted the Bcl-2/Bax balance and activated caspase-3. Based on these mechanisms, PPD effectively suppresses angiogenesis [ 90 ]. In addition to its protective and regulatory roles in vascular tissues, PPD also modulates the blood coagulation cascade and functions as a potent hemostatic agent. In vivo studies demonstrated that PPD significantly shortened bleeding time in both mouse tail amputation and liver injury models, while also increasing circulating platelet counts. Moreover, PPD enhanced systemic coagulation by reducing activated partial thromboplastin time (APTT) and elevating fibrinogen (FIB) levels. At the cellular level, PPD directly induced aggregation of human platelets and promoted dense granule release of ATP. It also significantly increased the expression of key platelet activation markers, including P-selectin (CD62P) and PAC-1. Mechanistically, these pro-coagulant effects were mediated through activation of the platelet surface receptor protease-activated receptor-1 (PAR-1), which triggered intracellular Ca 2+ influx and subsequently activated the PI3K/AKT and p38 MAPK signaling pathways, ultimately leading to enhanced platelet aggregation and efficient hemostasis [ 91 ]. Ginseng exhibited a strong therapeutic effect on skin damage [ 92 ]. Among the bioactivity compounds, PPD exhibits significant therapeutic potential in dermatology, including protection against environmental skin damage and chronic wounds. Environmental ultraviolet (UV) radiation is a major cause of skin aging, as it induces strong oxidative stress and progressive structural damage in skin tissues. Some studites have reported that PPD exhibited notable anti-photoaging activity by protecting epidermal keratinocytes (HaCaT cells) from UV irradiation. Mechanistically, PPD markedly suppressed extensive ROS induced by UV, thereby reducing oxidative stress in skin cells. Meantime, this suppression effect also prevented cellular senescence in underlying human dermal fibroblasts. The mechanistic studies demonstrated that PPD significantly suppressed the expression of MMPs by inhibiting MEK1/2–ERK1/2–p90RSK2 and MEK3/6–p38 MAPK pathways, thereby preventing collagen degradation and preserving extracellular matrix integrity. Collectively, these effects contribute to the protection of skin structure and the inhibition of photoaging [ 93 ]. Although PPD suppresses abnormal angiogenesis in tumors, it promotes controlled vascular growth during tissue repair. In full-thickness excisional wound models, PPD treatment significantly promoted wound healing compared with untreated controls [ 94 ]. This regenerative effect is particularly important in diabetic wounds, where impaired angiogenesis and inflammation often delay healing. Mechanistically, PPD stimulated neovascularization by activating the PI3K/AKT/mTOR and Raf/MEK/ERK signaling pathways. These pathways converged on p70S6 kinase, which stabilized HIF-1α and enhanced the secretion of vascular endothelial growth factor (VEGF), thereby promoting the formation of new blood vessels and restoring the damaged vascular network [ 95 ]. To improve its therapeutic effects in wound repair, several advanced topical delivery systems have been developed. Sun et al. incorporated PPD into nanostructured lipid carriers (NLCs) enhancing diabetic wound healing by accelerating re-epithelialization and regulating collagen remodeling, which ultimately reduced scar formation [ 96 ]. Recently, microfluidic-engineered nanocomposite hydrogel microspheres (PPD-Lipo@HMs) have been designed to further improve local delivery. In diabetic wound models, this system not only enhanced angiogenesis but also modulated the immune microenvironment by promoting the polarization of macrophages toward the pro-healing M2 phenotype. This shift alleviated chronic inflammation and promoted granulation tissue formation, thereby significantly improving tissue regeneration [ 97 ]. Beyond epidermal repair, PPD also shows strong potential in the treatment of androgenetic alopecia (AGA). Zhang et al. developed a “drug–carrier integration” delivery system for the treatment of alopecia. In this design, cholesterol-free liposomes were engineered in which PPD simultaneously functioned as a structural stabilizer of the lipid bilayer, replacing cholesterol, and as the active therapeutic compound. Specifically, PPD promoted hair regrowth primarily by activating the Wnt/β-catenin signaling pathway while exerting local anti-inflammatory effects. This strategy provides a promising and safer topical approach for hair loss treatment [ 98 ]. PPD demonstrates significant therapeutic efficacy against metabolic syndrome. Its pharmacological activities include the treatments of obesity, hyperlipidemia, hepatic steatosis, and insulin sensitivity [ [99] , [100] , [101] , [102] , [103] , [104] ]. PPD exhibits potent anti-obesity activity by modulating both central appetite regulation and cellular metabolic stress responses. In high-fat diet (HFD)-induced obese mice, systemic administration of PPD significantly reduced body weight, adiposity, and food intake. Mechanistically, Liu et al. demonstrated that this anorexigenic effect was centrally mediated. Intracerebroventricular administration of PPD rapidly activated neurons within the paraventricular nucleus (PVH) of the hypothalamus, thereby suppressing feeding behavior and promoting energy expenditure [ 99 ]. Besides, Jin et al. indicated that PPD further suppressed obesity by regulating metabolic stress. Specifically, it activated the GCN2 and PERK signaling pathways to induce the expression of Sestrin2 (Sesn2), which promotes AMPK activation, autophagy, and metabolic health [ 100 ]. In the liver and systemic circulation, PPD effectively alleviates lipotoxicity and lipid metabolic disorders. In HFD models, PPD significantly decreased serum levels of total cholesterol, triglycerides, and LDL-C, while increasing the level of protective HDL-C, which suggested the anti-hyperlipidemic effect. Mechanistic studies indicated that this effect was associated with remodeling of the gut microbiota, particularly the enrichment of Akkermansia muciniphila ( A . muciniphila ). In addition, PPD regulated bile acids metabolism through the FXR/CYP7A1 signaling pathway, decreasing total bile acids levels and altering bile acids enterohepatic circulation in HFD-fed rats [ 101 ]. And in HepG2 cells exposed to elevated free fatty acids, PPD significantly reduced intracellular lipid accumulation by suppressing oxidative stress and enhancing lipid clearance pathways, suggesting the therapeutic potential for hepatic steatosis [ 102 , 103 ]. In adipocytes and myotubes, PPD enhances glucose utilization and restores insulin sensitivity. Lee et al. reported that PPD significantly increased glucose consumption in both 3T3-L1 adipocytes and C2C12 myotubes under palmitic acid (PA)-induced insulin-resistant conditions, by activating the AMPK and PI3K/AKT signaling pathways [ 103 ]. In addition, PPD protects pancreatic β-cells from lipotoxic injury. In PA-treated INS-1 β-cells, PPD significantly inhibited the apoptosis and restored PDX-1 expression and insulin secretion by activating PI3K/AKT pathway [ 104 ]. These studies show the insulin regulatory effect of PPD. PPD exhibits nephroprotective effects, including the therapeutic potential against renal fibrosis, acute kidney injury (AKI), and immune-mediated glomerular diseases [ [105] , [106] , [107] , [108] , [109] ]. In chronic diabetes, hyperglycemic conditions typically promote extracellular matrix deposition. However, PPD treatment effectively mitigates this fibrotic response. In primary mesangial cells, PPD suppressed high-glucose-induced fibronectin accumulation by inhibiting the MAPK and PI3K/AKT signaling pathways [ 105 ]. Furthermore, Li et al. reported the anti-fibrotic effect and underlying mechanisms of PPD in vivo and in vitro , based on network pharmacology, molecular docking, and experimental validation. This study indicated that PPD significantly alleviated renal fibrosis in db/db mice and HK-2 cells by inhibiting the TGF-β/Smad pathway [ 106 ]. Collectively, these results indicate that PPD exerts significant anti-renal fibrotic effects. Beyond chronic metabolic injury, PPD also protects the kidney from acute nephrotoxicity. In cisplatin (CDDP)-induced AKI models, PPD administration significantly improved renal filtration function, promoted tissue repair, and reduced oxidative stress in both mice and HK-2 cells. Mechanistically, PPD suppressed lipid peroxidation and protected renal tubular epithelial cells, by limiting intracellular free iron accumulation and activating GPX4/FSP1 antioxidant system [ 107 ]. PPD also functions as an effective immunomodulator in immune kidney diseases, including lupus nephritis and nephrotic syndrome. In MRL/lpr mice with lupus nephritis, PPD alleviated disease progression by improving renal function and suppressing the abnormal proliferation of glomerular mesangial cells by inhibiting PTX3/MAPK/ERK1/2 signaling pathway [ 108 ]. In addition, in Adriamycin (ADR)-induced nephrotic syndrome, PPD protected glomerular podocytes from structural injury, as evidenced by decreased desmin expression and increased synaptopodin levels. Notably, the combination treatment with PPD and prednisone exhibited a significant synergistic effect. Here, PPD enhanced the anti-inflammatory effect of prednisone by inhibiting NF-κB activation. Meantime, PPD also avoided excessive GR transactivation induced by prednisone [ 109 ]. Liver fibrosis is characterized by excessive extracellular matrix deposition driven primarily by the activation of hepatic stellate cells (HSCs). PPD exhibits potent anti-fibrotic activity in the liver by suppressing HSC activation and fibrogenic signaling. In CCl 4 -induced hepatic fibrosis models, PPD treatment significantly alleviated liver fibrosis by inhibiting the activation of HSCs. Mechanistically, PPD significantly suppressed the TGF-β/Smad signaling pathway by binding to the ATP-binding pocket of TGFβR1 kinase [ 110 ]. In addition, PPD regulated epigenetic modification by inhibiting DNMT1, resulting in the demethylation and the reactivation of WIF1. This activation further inhibited the Wnt/β-catenin pathway, thereby preventing HSC activation [ 111 ]. PPD also induced apoptosis in activated HSCs by activating the LKB1/AMPK/mTOR pathway and promoting ROS generation [ 112 ]. Moreover, in HFD-induced (non-alcoholic fatty liver disease) NAFLD mice, PPD regulated lipid metabolism by activating the AMPK/SIRT1 signaling pathway, which was further confirmed by in vitro experiments [ 113 ]. In the lung, PPD also demonstrates clear anti-fibrotic activity. In bleomycin (BLM)-induced pulmonary fibrosis models, PPD preserved alveolar structure and reduced collagen deposition. Through modulation of the gut–lung axis, PPD regulated the gut microbiota to generate metabolites that activated the AMPK/STING signaling pathway in lung tissue. This activation suppressed NF-κB-mediated inflammation and TGF-β1/Smad-dependent fibrotic signaling, thereby alleviating pulmonary fibrosis [ 114 ]. Furthermore, PPD suppressed G6PD-driven glycolytic reprogramming by directly inhibiting the SPHK1/S1P/mTOR signaling pathway [ 11 ]. PPD effectively prevents inflammation-induced bone loss. In titanium particle–induced aseptic loosening models, PPD treatment significantly alleviated bone loss by suppressing osteoclast genesis. Specifically, PPD dose-dependently inhibited the formation of F-actin rings and reduced TRAP-positive osteoclasts. Mechanistically, PPD inhibited the MAPK and NF-κB signaling pathways by targeting TAK1, thereby promoting osteoclast differentiation and inflammatory responses [ 115 ]. A similar protective effect has been observed in periodontitis. Huangfu et al. developed carrier-free nanoparticles composed of PPD and resveratrol for the treatment of periodontitis. In Porphyromonas gingivalis ( P. gingivalis )–induced periodontitis mice, local administration of these nanoparticles scavenged excessive ROS and promoted macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, thereby reducing inflammation and preserving the structural integrity of the periodontal ligament [ 116 ]. Endometriosis is an estrogen-dependent inflammatory disease. In ectopic endometrial stromal cells (eESCs), PPD restored hormonal balance and suppressed the viability of endometriotic lesions by downregulating ERα and upregulating progesterone receptor (PR). This modulation also reversed the inhibition of autophagy induced by estrogen. Meantime, PPD enhanced local immune surveillance by restoring the cytotoxic activity of NK cells against ectopic endometrial tissue [ 117 ]. In addition, Lai et al. indicated that PPD remodeled fertility by ESR and PGR-mediated regulation of endometrial receptivity and inflammation response of peritoneal Mφ, and prevented pregnancy loss by increasing decidualization-associating genes expression and promoting proliferation and function regulation NK cells [ 118 ]. Ginseng extracts exhibit the immune regulative effect [ [119] , [120] , [121] , [122] , [123] , [124] , [125] , [126] , [127] , [128] ]. And many studies have demonstrated that the main bioactivity compound is PPD. By binding to the GR, PPD efficiently suppressed NF-κB–mediated inflammatory responses through transrepression. Importantly, PPD largely avoids classical transactivation and the associated metabolic side effects induced by glucocorticoids. It indicated that PPD could be considered as potent and selective GR agonist [ 129 ]. In addition to its anti-inflammatory activity, PPD also enhances the systemic immune response. Jiang et al. reported that PPD promoted immune competence and enhanced NK cell activity by activating NF-κB signaling pathway [ 130 ]. In CTX-induced immunosuppression models, PPD effectively reversed spleen and thymus atrophy and restored bone marrow hematopoiesis. Mechanistically, PPD promoted the generation of immunoregulatory metabolites (e.g., ceramides) by regulating gut microbiota, resulting in subsequently stimulating hematopoietic proliferation and normalizing circulating leukocyte levels [ 9 ]. In retinopathy, PPD demonstrates protective effects against chloroquine (CQ)-induced vision loss. In ARPE-19 retinal pigment epithelial (RPE) cells, PPD dose-dependently mitigated CQ-induced cytotoxicity, effectively recovered CQ-induced disruptions such as lysosomal alkalinization, impaired enzymatic activity, and excessive accumulation of ROS. Mechanistically, PPD restored lysosomal acidity and normalized autophagic flux by activating the AMPK/mTOR pathway. Besides, PPD inhibited ROS induced apoptosis by promoting autophagy and regulating the Beclin-1/Bcl-2 complex. These findings suggest that PPD is a promising treatment strategy for CQ-induced retinopathy [ 131 ]. Ginseng exhibited a strong anti-aging effect [ 132 , 133 ]. And PPD might be the main compound in ginseng of this effect. Using the classic aging model Caenorhabditis elegans ( C . elegans ), Song et al. demonstrated that PPD treatment significantly prolonged the healthy lifespan of nematodes. Besides, PPD also enhanced stress resistance, significantly improving survival under the environmental challenges such as acute heat shock and oxidative stress. Mechanistically, PPD exerted this anti-aging effect by activating the DAF-2/insulin/IR axis. Besides, molecular docking and in vivo analyses revealed that PPD directly interacted with the insulin receptor homolog DAF-2, thereby attenuating downstream kinase signaling and promoting the nuclear translocation of DAF-16/FOXO. And this translocation further activated the antioxidant defense genes, reducing the oxidative damage and ultimately extending lifespan and health span [ 134 ].

Several studies have investigated the pharmacokinetic characteristics of PPD in animal models. After oral administration of 2 mg/kg in rats, PPD reached a peak plasma concentration (C max ) of 130.2 ng/mL at 150 min (T max ), with an absolute oral bioavailability of 36.8 ± 12.4%. Following intravenous administration at 0.2 mg/kg, the elimination half-life (T 1/2 ) was 163.9 min and the pharmacokinetic profile conformed to a two-compartment open model [ 135 ]. However, another study reported a longer T 1/2 of 4.22 ± 1.15 h after intravenous administration at a much higher dose (25 mg/kg), which was likely related to the dose difference and the vehicle used to dissolve PPD [ 136 ]. Formulation also plays an important role in the pharmacokinetics of PPD. Compared with conventional formulations, emulsion and oil-based formulations showed faster absorption and higher C max values (1114.19 ± 152.92 ng/mL and 708.27 ± 136.61 ng/mL, respectively), resulting in improved absolute bioavailability (22.37% and 20.74%) [ 136 ]. In another study, the oral bioavailability of PPD reached 48.12%, which was attributed to improved solubilization by the Solutol® HS 15 excipient and possible metabolic interaction with co-administered (20S)-protopanaxatriol (PPT) [ 137 ]. Other studies reported lower bioavailability values (27.3 ± 13.4%), suggesting that absorption is strongly influenced by formulation and experimental conditions [ 138 ]. Specially, when three different PPD formulations were compared at 25 mg/kg, hydroxypropyl-β-cyclodextrin (HP-β-CyD) inclusion complexes and pharmacosomes showed higher oral bioavailability (49.0% and 42.6%) than the conventional PPD solution (DMSO and Tween 80) (40.0%) [ 139 ]. A similar improvement was observed with HP-β-CyD formulations in another study, which also reported a “double-peak phenomenon” in the plasma concentration–time curve, possibly caused by enterohepatic recirculation [ 140 ]. In a recent study evaluating pharmacokinetics in rats and dogs, oral bioavailability in rats was approximately 28.5%, while a lower value (11.0%) was observed in dogs. Tissue distribution studies indicated that PPD did not accumulate significantly in major organs 24 h after administration, and only minimal amounts were detected in urine, feces, or bile, suggesting that PPD is mainly cleared through metabolism [ 12 , 141 ]. Clinical pharmacokinetic data for PPD are limited but provide important insights. The first human pharmacokinetic study reported that PPD was absorbed relatively quickly after oral administration (25 mg), reaching a C max of 7.24 ± 3.30 ng/mL at a T max of 1.28 ± 0.49 h. The elimination half-life was approximately 4.77 ± 2.05 h, and the total exposure (AUC 0–∞ ) was 25.0 ± 13.8 (ng h)/mL [ 142 ]. A later clinical study evaluated single oral doses of 100, 200, and 400 mg. The results showed dose-proportional pharmacokinetics, with C max and AUC increasing linearly with dose. The T max ranged from 3.5 to 4.4 h and the T 1/2 ranged from 10.6 to 16.5 h, which are higher than the first clinical study. These findings further demonstrate that the pharmacokinetics of PPD are dose dependent. Similar to observations in animal studies, a clear “double-peak phenomenon” was detected in the plasma concentration curve, which may be related to hepatic or enterohepatic circulation [ 140 , 143 ]. In a Phase IIa clinical trial investigating PPD as an antidepressant, steady-state plasma concentrations were measured in patients after continuous oral administration of different doses for six weeks. The results confirmed a strong linear relationship between the daily dose and steady-state plasma concentration, supporting dose-proportional pharmacokinetics in humans [ 144 ]. Extensive metabolism is a major characteristic of PPD disposition. In rat studies, only trace levels of the parent compound were detected in plasma, and it was not detected in bile, urine, or feces, indicating that PPD undergoes extensive metabolism before excretion. A total of 23 metabolites were identified in plasma, bile, urine, and feces, including 16 newly reported metabolites. The main metabolic pathways included oxidation, dehydrogenation, and glucuronidation [ 12 ]. Subsequent studies further expanded the metabolic profile of PPD. Up to 29 metabolites were identified, confirming extensive Phase I reactions such as monooxygenation and dioxygenation, as well as Phase II reactions including glucuronidation. Several major metabolic routes were proposed, including the formation of 20,24-oxide metabolites, oxidation of the side chain to carboxylic acid derivatives, and direct glucuronidation. In addition, cysteine conjugation was identified as a novel Phase II metabolic pathway [ 145 ]. The stereoselective metabolism of PPD has also been reported. Two major ocotillol-type epimers, the 24S-epimer and 24R-epimer, are formed during metabolism, with the 24S-epimer being the predominant metabolite in plasma [ 146 ]. In vitro metabolic studies have suggested that oxidation is the major Phase I pathway, followed by hydrolysis and rearrangement to form 20,24-oxide derivatives [ 147 ]. However, the occurrence of direct glucuronidation remains controversial, as some studies reported that PPD cannot undergo direct glucuronidation, whereas others identified PPD-3-O-β-D-glucuronide as a major Phase II metabolite [ 13 , 147 ]. More recent analytical studies have identified additional oxidative metabolites in rat plasma, including mono-, di-, tri-, and tetra-oxygenated products, as well as dehydrogenation derivatives. These findings again confirmed that 20,24-oxide epimers are among the major metabolites of PPD [ 148 ]. Quantitative analysis further showed that the parent compound remains the most abundant component in plasma, followed by the 24S-epimer, the 24R-epimer, and PPD-glucuronide [ 149 ]. Importantly, a clear species difference has been observed in PPD metabolism. In humans, metabolism is also dominated by Phase I oxidation reactions leading to multiple 20,24-oxide derivatives. However, unlike in rats, Phase II metabolites such as glucuronides were not detected in human plasma or urine. In addition, the parent compound was not detected in urine, suggesting that PPD is almost completely metabolized through hepatic Phase I pathways before excretion [ 147 ]. Because PPD undergoes extensive hepatic metabolism, its potential interaction with cytochrome P450 enzymes has also attracted attention. PPD may influence the metabolism of other drugs through interactions with cytochrome P450 enzymes. Computational molecular docking studies suggested that PPD could act as a competitive inhibitor of CYP2C9 and a weak inhibitor of CYP3A4 [ 150 ]. However, experimental studies have reported stronger inhibitory effects on CYP3A4, which may affect the metabolism of co-administered drugs such as calcitriol [ 151 ]. In addition, inhibition of CYP3A4 and CYP2B6 by PPD has also been reported, indicating a potential risk of drug–drug interactions that requires further investigation [ 152 ].