The narrative review was performed through electronic database searches (PubMed, Scopus, Web of Science, Google Scholar, and Sci-Finder), with the date range of publication from the beginning of the database to December 2025. The search terms used included the combinations of the Project TAG with the search triggers of Structure Activity Relationship (SAR), pharmacological properties, anti-tumor, anti-inflammatory, antimicrobial, hepatoprotective, pharmacokinetics, toxicology, and pre-clinical studies (which included both in vitro studies and in vivo studies) via the use of “abietic acid” as the trigger word. All languages were reviewed; however, the only articles that were reviewed were in the English language. The inclusion criteria were research articles, reviews, and studies that described the chemical structures, biological activity, pharmacokinetics, and toxicity of AA studied in preclinical models. The exclusion criteria for this review were non-peer-reviewed literature, studies on compounds not related to AA, and studies that did not provide enough data to be considered as studies. Approximately sixty relevant articles were selected for inclusion based on relevance and quality; however, because the authors wanted to focus on publishing up-to-date material, they prioritized those articles published after 2015. The authors did not conduct a formal meta-analysis, as this research narrative is a narrative review, but they synthesized the information from the included studies by thematic analysis of the information. The reference lists for the studies that met the inclusion criteria were also evaluated for additional studies.

The basis for AA activity is the tricyclic phenanthrene-like scaffold which has two angular methyl groups on the C-16 and C-17 positions (Gaborova et al., 2021; Zentar et al., 2022). The overall rigid, planar structure permits π-π stacking interactions within hydrophobic binding pockets of specific proteins that increase specificity and binding affinity (Rahaman et al., 2024). The chair-boat conformation of the cyclohexane ring allows for adaptable binding to distinct biological entities. The extended conjugated diene structure (i.e. Δ7,8 and Δ13,14) allow for electron delocalization that increases free radical scavenging potential and increases capacity for generating reactive oxygen species (ROS), a characteristic that is plausible in cancer cell ferroptosis induction (Xu et al., 2023).

The scaffold’s natural hydrophobicity allows selective partitioning into lipid bilayers, which can then modulate membrane-associated signaling pathways. This property is essential for AA to accumulate in cellular membranes and impact processes like inflammation and apoptosis. Structural analogs of AA, such as dehydroabietic acid, which share the same core but have distinct oxidation states, have demonstrated similar or greater antimicrobial and anti-inflammatory properties compared to AA, demonstrating the diverse applications of the scaffold. Of note, the planar scaffold may also inhibit AA’s solubility and bioavailability leading to challenges in pharmaceutical development. Optimizations, such as nanoparticle-based AA delivery, have been utilized to enhance AA delivery and efficacy, providing an understanding of the tradeoff between scaffold rigidity and drug formulation/development (Hao et al., 2022).

The carboxylic acid group at C-18 is a vital pharmacophore that dictate AA’s electronic properties, as well as its solubility and interactions related to molecular activity. In its ionized form as a carboxylate, it is responsible for pH-dependent interactions with inflammatory mediators, such as inhibiting the activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and reducing the production of TNF-α (tumor necrosis factor-alpha) and IL-1β (interleukin-1 beta) (An et al., 2023). Esterifying or removing this group eliminates anti-inflammatory effects, indicating its importance in target binding.

Additionally, the carboxylic acid group is instrumental in AA’s properties as an antioxidant and a regulator of ferroptosis. The carboxylate group provides the ability for free radical scavenging via proton-coupled electron transfer, and the ability to chelate Fe²⁺ minimizes labile iron pools and limits processes such as lipid oxidation, ultimately reducing the formation of 4-hydroxynonenal (Shi et al., 2014; Zhang et al., 2023). Furthermore, the carboxylic acid group promotes enhanced binding of AA to discrete enzymes such as GPX4 (glutathione peroxidase 4) through hydrogen bonding at the active site (where there is a selenocystine), allowing for enhanced anti-ferroptotic effects observed in AA, compared to other non-acidic diterpenoids (Shi et al., 2014; Zhang et al., 2023).

In terms of pharmacokinetic properties and microenvironment, the ionization of this functional group enables AA to cross biological barriers, while simultaneously permitting enough hydrophilicity for aqueous reactivity (Villalain, 1997). Structural studies demonstrate that the planar arrangement between the carboxyl and adjacent methyl positions yields a stereo electronic environment that is best suited for “dual” interactions with biological targets, in both hydrophilic and hydrophobic environments (Labrecque and Fuglestad, 2021; Zhang et al., 2023). This dual functionality underscores the carboxylic acid as a multifunctional moiety essential for AA’s pleiotropic actions.

The hydrophobic properties of AA, which include the isopropyl group (C-13) and methyl groups (C-10 and C-16), are important determinants for AA’s membrane permeability and binding efficiency to target proteins. The β-orientated isopropyl group interacts with the hydrophobic pocket of proteins, such as IKKβ (IκB kinase beta), which stabilizes the binding complex through van der Waals forces and enhances a broad range of effects involving anti-inflammatory signal transduction (Jung et al., 2022; Kang et al., 2018). The C-10 methyl group also helps conformationally stabilize the A ring and protects the carboxylic acid functional group from a nucleophilic attack, reducing the consumption of AA’s reactive carbons (Rafferty et al., 2013).

Notably, the hydrophobic “clamp” formed by the C-10 methyl and C-13 isopropyl groups provides a two-fold increase in the activation of PPARγ (peroxisome proliferator-activated receptor gamma) by simultaneously engaging the Leu330 and Phe363 residues of the ligand-binding domain (Fernandez, 2014). Additionally, the conjugated double bonds (Δ7,8 and Δ13,14) promote π-π stacking with aromatic amino acids contributing approximately 15% of the total binding energy (Gonzalez et al., 2009; Huang et al., 2017). Additionally, the Δ13,14 double bond provides stable planarity that is optimal for recognition by the target protein, which is demonstrated by the loss of activity by saturation analogs (Gonzalez et al., 2009).

The hydrophobic residues also facilitate the incorporation of AA into lipid membranes modulating AA’s pharmacological effects on membrane-bound receptors and enzymes. At the same time, excessive hydrophobicity may decrease aqueous solubility, which may require structural trade-offs. Semisynthetic modifications, such as introducing polar substituents to the isopropyl group, have yielded derivatives with improved bioavailability and retained activity, illustrating the potential for rational optimization.

The stereochemical configuration of AA determines its 3D orientation and target selectivity (Tapia et al., 2014). The 4R chiral center and position of the C-4 methyl group enables stabilization of the C-ring in a half-chair conformation to maximize the hydrogen bonding network of the carboxylic acid with Ser177 residue in PPARγ (Fernandez, 2014; Masnyk et al., 2018; Thummuri et al., 2018). Molecular docking studies support that the R-configuration at C-9 establishes optimal hydrophobic packing into the PPARγ ligand-binding domain and results in transcriptional activation (Jeon et al., 2015).

The chiral crown conformation of AA’s tricyclic system is even capable of differential engagement with distinct targets: the concave β-surface engages with the helix 3/β-sheet region of the PPARα (peroxisome proliferator-activated receptor alpha) target, while the convex α-face of AA engages with TRPV1 channels via van der Waals forces (Masnyk et al., 2018; Oyama et al., 2021; Wang et al., 2011). This stereospecificity is important in selectivity for PPARγ over LXRβ (liver X receptor beta) and for minimizing off-target effects (Ohashi et al., 2010; Yue et al., 2005). For example, simple epimerization at C-4a can completely obliterate NF-κB inhibition, demonstrating the sensitivity of bioactivity to stereochemistry change.

Asymmetric synthetic methodologies that produce stereoisomers for SAR have advanced to the point where we can now show that minor chiral changes can result in dramatic alterations in potency and selectivity. Future advances to utilize the stereochemical features of AA may lead to highly specific modulators of metabolic and inflammatory pathways. The brief SAR of AA is illustrated in Figure 2.

Studies show that AA exhibits cytotoxicity on a wide variety of cancer cells but has little effect on normal cells, suggesting a favorable therapeutic window. The mechanisms of its anticancer effect are complex and vary among cancer cell types, including induction of programmed cell death, cell cycle inhibition, anti-metastatic activity, and modulation of various oncogenic signaling pathways.

One interesting observation is the ability of AA to induce ferroptosis, which is a form of programmed cell death that is iron-dependent, in bladder cancer cells. Xu et al. reported that AA selectively reduced the viability of bladder cancer cells (e.g., by 50%–70% in T24 and 5637 cell lines at 10–20 μM) but did not have an effect on the normal urothelial cells (Xu et al., 2023). This effect was mediated by upregulation of heme oxygenase-1 (HO-1), followed by downregulation of glutathione peroxidase 4 (GPX4) and accumulation of ROS, lipid peroxidation, and iron overload, which are all biomarkers of ferroptosis. The criticality of this pathway was shown when forced expression of GPX4 or pharmacological inhibition of HO-1 attenuated ferroptosis from AA. AA also acted synergistically with classical chemotherapeutics such as cisplatin and gemcitabine and reduced in vivo tumor growth in xenograft mouse models, making it a promising candidate for bladder cancer treatment (Xu et al., 2023).

In non-small cell lung cancer (NSCLC), AA inhibited cell proliferation and colony formation by blocking the IKKβ/NF-κB signaling pathway. Liu et al. showed that AA bound directly to IKKβ, leading to decreased phosphorylation of IKKβ and the inhibition of NF-κB nuclear translocation (Liu et al., 2019). NF-κB is a key modulator of genes regulating apoptosis and cell growth, thus, the intervention of the IKKβ/NF-κB pathway resulted in apoptosis as indicated by G0/G1 phase cell cycle arrest, decreased Bcl-2, and PARP (poly (ADP-ribose) polymerase) cleavage. Furthermore, overexpression of IKKβ reversed the tumor inhibitory effects of AA, showing that inhibition of IKKβ onset AA cytotoxicity. Computational molecular dynamics simulations suggested that hydrophobic interactions, among other factors, drive the binding interaction of AA and IKKβ (Liu et al., 2019).

AA’s antimetastatic capability further enhances its wide-ranging antitumor activity. For example, AA inhibited cell migration, invasion, and motility in vitro in melanoma even without negatively affecting cell viability at the antimetastatic levels (Hsieh et al., 2015). Inhibition of migration, invasion, and motility was consistent with decreased activities of the matrix metalloproteinase-2 (MMP-2) and the urokinase-type plasminogen activator; two highly involved enzymes associated with degradation of the extracellular matrix and promoting cancer dissemination. Furthermore, inhibition of these proteases coincided with the inhibition of the PI3K/Akt (phosphatidylinositol 3-kinase/protein kinase B) signaling pathway and decreased DNA binding activity of the transcription factor AP-1 (activator protein-1). Furthermore, AA decreased lung metastasis of B16F10 melanoma cells by approximately 92.8% in vivo when administered orally, demonstrating the potential to inhibit cancer dissemination (Hsieh et al., 2015).

Similar mechanisms have been observed in other cancer types. For instance, in nasopharyngeal carcinoma, AA also induced G2/M phase cell cycle arrest and mitochondrial-mediated apoptosis ascribed to the generation of ROS, loss of mitochondrial membrane potential and activation of caspases-3 and -9 (Wen et al., 2019). AA also significantly inhibited migration and invasion of NPC cells (e.g., reducing invasion by up to 60% at 20 μM) and inhibited the PI3K/Akt/mTOR (mammalian target of rapamycin) pathway which is a key regulator of cell growth and survival. In addition, AA showed chemopreventive activity in a mouse model of skin cancer in which AA inhibited DMBA (7,12-dimethylbenz [a]anthracene) and UVC-induced tumor formation likely through downregulation of MMPs (matrix metalloproteinases) and cytokeratin (Yang and Tian, 2017).

The evidence for the antitumor effects of AA is robust and a result of a complex interplay of mechanisms including induction of ferroptosis, apoptosis, cell cycle arrest, inhibition of key signaling pathways such as IKKβ/NF-κB and the PI3K/Akt/mTOR pathway, and inhibition of metastasis. The preferential effects on cancer cells and the ability to synergize with existing chemotherapeutics add to the therapeutic appeal of AA. Nonetheless, while preclinical data are optimistic, more research is needed to fully understand its pharmacokinetics, assess in vivo efficacy in various cancer models and assess potential toxicities before finally translating AA to the clinic (Figure 3).

Numerous preclinical investigations using diverse inflammatory models have confirmed the anti-inflammatory effects of AA. The initial study showed that AA concentration-dependently inhibited protein denaturation and protected in vitro human red blood cell membranes, a classic mechanism of anti-inflammation, providing strong evidence for membrane-stabilizing effects (Hasan et al., 2024a). Moreover, this study showed that AA reduced formalin-induced paw edema (e.g., by 40%–60% at 20–40 mg/kg) and pain-related behaviors in chicks in vivo. Notably, AA was an antagonist to traditional non-steroidal anti-inflammatory drugs (NSAIDs), including celecoxib and ketoprofen. The effects of NSAIDs were diminished when combined with AA. Moreover, molecular docking and dynamics simulations provided structural support for AA’s antagonistic activity on celecoxib and ketoprofen by showing that AA binds to COX-2 (cyclooxygenase-2) with high affinity, similar to celecoxib, and forms a stable complex with COX-2, suggesting a primary mechanism of direct enzyme inhibition (Hasan et al., 2024a).

The anti-inflammatory effects of AA extend beyond COX inhibition and appear to be crucially mediated through the modulation of key transcription pathways. AA has been shown to act as a dual activator of PPARα/γ. In human dermal fibroblasts, AA inhibited UVB-induced expression of matrix metalloproteinase-1 (MMP-1) via inhibition of the MAPK (mitogen-activated protein kinase) pathway, along with its downstream effectors, activator protein-1 (AP-1) and NF-κB. The effects of AA were shown to be PPARα/γ-dependent, as antagonists of the PPARs, GW6471 and BADGE, blocked the inhibitory actions of AA on MMP-1 expression and inflammatory signaling (Jeon et al., 2015). The inhibition of NF-κB was additionally characterized by AA-mediated inhibition of degradation of the NF-κB inhibitory protein IκBα, as well as prevention of nuclear translocation of the p65 subunit.

AA’s potential pharmacological effects on inflammation have been assessed in various disease-specific inflammatory models. In a model of allergic asthma induced by ovalbumin (OVA), AA treatment reduced airway hyper-responsiveness (e.g., by 50%–70% at 10–40 mg/kg), reduced inflammation and the number of inflammatory cells in bronchoalveolar lavage fluid (eosinophils, neutrophils, lymphocytes), and reduced Th2 cytokines (IL-4, IL-5, IL-13), OVA-specific IgE, and nitric oxide (NO). These effects of AA in ameliorating asthma symptoms were attributed to the inhibition of NF-κB in lung tissues (Gao et al., 2016). In a separate model of atopic dermatitis induced by chemical (2,4-dinitrochlorobenzene, DNCB), AA made into a cream and applied topically was found to reduce skin lesions, dermatitis scores, and serum IgE. These beneficial effects were attributed to suppressing the inducible nitric oxide synthase (iNOS)-COX-2 pathway, and reductions in the transcriptional levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-10), as well as inhibition of NLRP3 (NOD-like receptor protein 3) inflammasome activation in skin tissues (Park et al., 2023). The effectiveness of AA on skin inflammation was also validated in an imiquimod-induced psoriasis model, where AA lowered the psoriasis area severity index (PASI) scores (e.g., by 30%–50% at 40 mg/kg), reduced epidermal thickness, rebalanced the Th17/Treg cell ratio in the spleen, and inhibited serum concentrations of IL-17A, IL-23, TNF-α and IL-1β (Li X. Q. et al., 2021). In addition, in human osteoarthritis chondrocytes, AA inhibited IL-1β-induced inflammation via the p38 MAPK signaling pathway, by decreasing TNF-α, NO, prostaglandin E2 (PGE2) and key enzymes that promote the degradation of the matrix (MMP-1, MMP-3, and MMP-13). Importantly, the PPARγ antagonist GW9662 reversed the anti-inflammatory actions of AA, indicating the involvement of the PPARγ pathway (Kang et al., 2018).

The body of evidence collectively supports AA as a multi-modal anti-inflammatory agent. AA’s effects may be due to a combination of direct enzymatic inhibition, activation of regulatory nuclear receptors, and downregulation of key pro-inflammatory signaling pathways. This multi-targeted action results in reduced expression and production of a broad array of inflammatory mediators, including pro-inflammatory cytokines, chemokines, NO, PGE2, and MMPs. The consistent efficacy of AA in multiple inflammatory conditions, including inflammatory skin conditions, respiratory conditions, and joint conditions, supports the potential therapeutic application of AA for a variety of clinical indications (Figure 4).

AA has a broad range of antimicrobial activity, especially against Gram-positive bacteria. For example, AA has been shown to have strong activity against Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA), with an MIC (minimum inhibitory concentration) range of 8–64 μg/mL based on the bacterial strain. Abietic acid’s activity is due to its ability to compromise the bacterial cell membrane. For example, AA was shown to increase uptake of fluorescence dyes such as SYTOX Green in membrane permeability testing, which indicated loss of membrane integrity (de Lima Silva et al., 2023a). Similarly, AA also exerted bacteriostatic activity against Staphylococcus pseudointermedius, reducing overall bacterial growth by up to 78% at 6 h in time-kill assays over several concentrations, but was not able to completely kill the bacteria (Buommino et al., 2021). Additionally, AA has activity against Gram-negatives, such as Pseudomonas aeruginosa, but at lower levels than corresponding Gram-positive species. The reduced activity is likely due to the structural differences in the cell wall; for example, biofilm viability was reduced by approximately 90% after 30 min of exposure to AA in quantitative biofilm assays (Dziegielewska et al., 2024).

Besides its antibacterial activity, AAis also a noteworthy antifungal agent, particularly in conjunction with a standard antifungal. In terms of Candida spp, such as Candida albicans and Candida tropicalis, AA alone was not significantly fungicidal (MIC > 1024 μg/mL), but was able to enhance fluconazole’s efficacy. Fluconazole’s IC₅₀ (half maximal inhibitory concentration) was over 1000 μg/mL alone when used alone, which was reduced to approximately 75–160 μg/mL in combination therapy. Part of the reason for this synergism is that a molecular docking study suggesting that AA interacts with lanosterol 14α-demethylase (CYP51), an important enzyme in ergosterol biosynthetic pathways, and potentiated fluconazole action through competitive inhibition (de Lima Silva et al., 2023a).

AA also inhibited fungal biofilm formation, as well as that of the oral bacterial pathogen Streptococcus mutans. This inhibition was measured through crystal violet staining, where biofilm biomass was reduced by approximately 99% at a concentration of 64 μg/mL (Ito et al., 2020). The antibiofilm effects could play an important role for treating persistent infections, since biofilms tend to be resistant to antimicrobials. AA’s antibiofilm properties are not limited to fungi but can also affect biofilms produced by bacteria in various contexts. For example, in ocular infection models, AA encased in bacterial cellulose carriers reduced S. aureus and P. aeruginosa biofilms on artificial eyeballs by as much as 80%, demonstrating its potential topical application (Dziegielewska et al., 2024). Similarly, with MRSP (methicillin-resistant Staphylococcus pseudointermedius), dissolved AA had a significant effect on the viability of preformed biofilms cultivated at sub-MIC doses (i.e., 20 μg/mL). After treatment, viability was reduced by 40%–80%, as determined by XTT assays and confirmed through confocal microscopy, which showed increased red staining implying dead cells embedded in the biofilm matrix (Buommino et al., 2021). These studies reveal that AA can penetrate biofilm matrices and kill organisms of clinical importance, which is a major advantage over many traditional antibiotics that cannot effectively penetrate biofilm resistance.

Although results are encouraging, the antimicrobial effects of AA are variable in terms of both bacterial species and exposure conditions. For example, AA was more effective against S. aureusthan it was against P. aeruginosa, and it also took longer for AA to affect C. albicans biofilms (24 h) when compared to the bacteria biofilms (30 min) (Dziegielewska et al., 2024). Along the same lines, in a number of situations, AA showed a bacteriostatic mode of action rather than that of a bactericidal agent. Specifically, with S. mutans, AA was able to inhibit growth and acid production, but without substantially compromising membrane integrity, which suggests that it may be better suited for preventative or adjunctive therapies as opposed to acute treatment (Ito et al., 2020). Notably, AA exhibited low cytotoxicity at the antimicrobial concentrations, up to 256 μg/mL in human fibroblasts and keratinocytes cell lines, which provides some evidence for its potential therapeutic safety. However, higher doses could be cytotoxic in monocytic cells.

AA can be considered a multi-faceted antimicrobial that could be used to treat bacterial and fungal infections, particularly due to its antibiofilm and synergistic mechanisms; however, more research is required on possible delivery systems and to evaluate efficacy in humans. Considering AA’s natural source and various mechanisms of action, it may be conceptualized as a beneficial addition to tackle antimicrobial resistance, thus research into its pharmacological applications can continue (Figure 5).

Among the several pharmacological effects of abietic acid, its beneficial hepatoprotective effects have been studied the most in different liver injury models. An et al. demonstrated that AA was protective against acetaminophen (APAP)-induced acute liver injury (An et al., 2023). In their studies, AA greatly reduced the pathological changes in the liver associated with APAP administration, such as necrosis and infiltrating inflammatory cells. There were also significantly lower serum levels of the enzymes ALT and AST (e.g., reduced by 50%–70% at 25–50 mg/kg), which are indicative of hepatic injury. Mechanistically, AA acted to diminish inflammation, represented by decreased production of TNF-α and IL-1β, and by blocking the NF-κB pathway. A unique feature of AA was its marked capacity to inhibit ferroptosis, which is a regulated form of cell death characterized by lipid peroxidation and iron accumulation. Importantly, AA treatment reversed the APAP-induced elevations of MDA (malondialdehyde) and Fe²⁺ while restoring the depletion of GSH (glutathione), ATP (adenosine triphosphate), and the expression of GPX4 and xCT (cystine/glutamate antiporter) expression. The beneficial effects of AA were shown to be dependent on the activation of the Nrf2/HO-1 (nuclear factor erythroid 2-related factor 2/heme oxygenase-1) axis, because the protective effects of AA were eliminated with Nrf2-knockout mice and Nrf2-knockdown hepatocytes. Overall, the evidence supports Nrf2 activation as a significant and beneficial mechanism underlying the hepatoprotective capacity of AA in the liver.

In addition to acute toxicant-induced injury, AA also has the potential to address liver injury associated with metabolic stress. Jung et al. explored the effects of AA on ER (endoplasmic reticulum) stress and lipid accumulation in human primary hepatocytes treated with palmitate, a treatment paradigm that models non-alcoholic fatty liver disease (NAFLD) (Jung et al., 2022). They found that exposure to AA decreased lipid accumulation and the levels of lipogenesis-related proteins such as SREBP1 (sterol regulatory element-binding protein 1) and SCD1 (stearoyl-CoA desaturase 1). AA also reduced ER stress induced by palmitate, as indicated by lower levels of phospho-eIF2α (phosphorylated eukaryotic initiation factor 2 alpha) as well as CHOP (C/EBP homologous protein), and decreased apoptosis. They elegantly showed that these effects were mediated through the AMPK/ORP150 (adenosine monophosphate-activated protein kinase/oxygen-regulated protein 150) signaling pathway. siRNA-mediated knockdown of either AMPK or ORP150 reversed the beneficial effects of AA on ER stress, lipogenesis, and apoptosis, thus confirming the importance of this axis. Overall, these findings suggest that AA can modulate hepatic lipid metabolism and ER homeostasis and may represent a future treatment option for individuals at risk of NAFLD.

The hepatoprotective activity of AA is also evident in models of inflammation. For example, Ramnath et al. found that AA reduced LPS (lipopolysaccharide)-induced liver injury in BALB/c mice (Ramnath et al., 2016). In their study, histopathological analysis showed that AA treatment prevented the lymphocytic infiltration and necrosis associated with LPS. The authors suggested that the protective effect may be attributed to the anti-inflammatory properties of abietic acid, possibly due to its hydroxyl groups, and may involve the reduction of inflammatory mediators such as NO.

AA is a naturally derived compound with diverse functions and substantial hepatoprotective potential against a range of insults, including drug overdoses and inflammation. Its mechanisms of action have common features that activate critical Nrf2/HO-1 pathways for antioxidant and anti-ferroptosis action, AMPK/ORP150 for alleviating ER stress and preventing lipid accumulation, and NF-κB for anti-inflammatory action. These crosstalk pathways underscore AA’s potential as a drug development candidate. It is important to point out that the evidence to date is based primarily on preclinical models. Further research is required to assess its therapeutic potential and advance to clinical models to determine translatability to human liver disease (Figure 5).

Recent research has demonstrated AA’s effectiveness through multiple mechanisms (e.g., promoting angiogenesis), and complex topical delivery systems have been developed to maximize its bioavailability and achieve sustained release at the wound site. A seminal study conducted by Park et al. directly demonstrated the pro-healing effects of AA in vitro and in vivo (Park et al., 2017). In this study, AA was found to significantly promote both cell migration (e.g., by 2-3 fold at 0.8 μM) and tube formation in human umbilical vein endothelial cells, which are essential steps in angiogenesis. The study linked the angiogenic effects of AA to the activation of key signaling pathways, mediated by upregulating phosphorylated extracellular signal-regulated kinase (p-ERK) and p38 mitogen-activated protein kinase. In addition, in a mouse model of cutaneous wounds, treatment with AA (0.8 µM) showed significantly increased rates of wound closure compared to controls, with accelerated healing noted as early as day two post-treatment. The authors reported that the wound closure effects were likely mediated through stimulating neovascularization, an important part of delivering nutrients and oxygen during tissue regeneration (Park et al., 2017).

Mirgorodskaya et al. addressed the challenge of formulating hydrophobic AA by developing and characterizing biocompatible microemulsions and emulgels as novel drug delivery systems (Mirgorodskaya et al., 2022). An important finding was that the microemulsions and emulgels containing a carbamate-containing surfactant and Carbopol® 940 significantly prolonged AA release. The sustained release profile was consistent with a near-zero order kinetic model, which would be favorable for sustaining effective drug concentrations over long periods of time. Furthermore, the formulations showed high antioxidant activity in tests using chemiluminescence, which may also allow for reduction of oxidative stress in the wound environment. In vivo effectiveness was demonstrated in a Wistar rat incision model: rats treated with topically applied AA-loaded formulations (0.5% wt.) showed rapid healing and doubled the tissue tensile strength compared to the untreated control group. The remarkable efficacy was attributed to a drug therapy that utilized the anti-inflammatory effects of AA combined with additional antibacterial effects from formulation components such as oleic acid (Mirgorodskaya et al., 2022).

The wound-healing properties of AA are twofold. First, it exerts direct biological effects by promoting angiogenesis—via activating MAPK signaling pathways—and stimulating the proliferation and migration of cells critical for tissue repair. Second, the incorporation of AA into microemulsions and emulgels improves its therapeutic use through sustained release and better adhesion to the skin, while additionally providing antioxidant and antimicrobial activity. Abietic acid’s natural pharmacological activity combined with the delivery system advantages make a strong argument for further investigating this topical agent in wound care. Future studies should consider clinical studies to demonstrate these promising preclinical findings and examine its potential in combination with other wound-healing agents (Figure 7).

Research has shown that AA may reduce hyperuricemia, pain, emesis, lung injury, osteoporosis, and diabetic nephropathy, primarily through modulation of key signaling pathways and molecular targets.

In hyperuricemia, AA has been shown to have inhibitory effects on xanthine oxidase (XO), which is an important enzyme for uric acid production. Indeed, Dai et al. identified AA from sunflower calathide extract that inhibited XO with an IC₅₀ of 10.60 µM and a Ki of 193.65 nM, with no cytotoxicity to HEK293T cells (Dai et al., 2023). Transcriptomics analysis showed AA modulates purine metabolism by suppressing purine nucleoside phosphorylase and ribose-phosphate pyrophosphokinase genes, suggesting there is a mode of action that goes beyond inhibiting XO and may regulate purine biosynthesis. The dual action of AA supports its potential as a natural alternative to conventional XO inhibitors like allopurinol.

AA exhibits substantial analgesic effects. Silva et al. found that administration of AA, at doses of 50, 100 and 200 mg/kg was able to reduce carrageenan-induced paw edema and decrease MPO (myeloperoxidase) levels in mice, which signified inhibition of neutrophil infiltration (de Lima Silva et al., 2023b). In dextran-induced edema models, AA antagonized histamine-dependent pathways, similar to promethazine, as well as partially inhibited eicosanoid-mediated responses. The compound was able to reduce nociception in formalin and acetic acid-induced writhing tests, indicating involvement of both neurogenic and inflammatory pain pathways, but none of these effects occurred with CNS depression. AA seems to provide improved safety compared to current NSAIDs considering the anti-inflammatory and analgesic effects.

Additionally, the antiemetic effect of AA has been evaluated in chick models where it was found to increase latency and reduce retching induced by copper sulfate. Hasan et al. found that both 5HT3 (5-hydroxytryptamine receptor 3) and muscarinic receptors were involved and supported this finding with molecular docking as AA had the highest binding affinity to M4 (−10.2 kcal/mol) and 5HT3 (−8.1 kcal/mol) compared to the reference drug ondansetron (Hasan et al., 2024a). This variation in receptor binding could help explain how it can synergize with other standard antiemetics for management of nausea and vomiting.

In lung injury models, AA possesses protective effects by regulating immune responses. Fang et al. noted that AA reduced sepsis-induced lung injury in mice by inhibiting activation of the NF-κB pathway, reducing the polarization of M1 macrophages, and promoting the shift towards M2 phenotype and reduced pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) (Fang et al., 2022). Likewise, Li et al. observed that AA restored the balance between Th17/Treg in an acute lung injury model via PPARγ activation while attenuating oxidative stress and inflammation (Li et al., 2022). These studies suggest that AA treatment may be beneficial in lung inflammatory diseases.

The osteoprotective effects of AA have been examined in osteoporosis models. Thummuri et al. showed that AA inhibited RANKL (receptor activator of nuclear factor kappa-B ligand)-induced osteoclastogenesis in RAW264.7 cells by inhibiting NF-κB and MAPK signaling, leading to reduced expression of osteoclast markers (TRAP (tartrate-resistant acid phosphatase), NFATc1 (nuclear factor of activated T-cells cytoplasmic 1)) (Thummuri et al., 2018). Furthermore, in vivo experiments revealed that AA reduced LPS-induced bone loss by reducing serum levels of TNF-α and IL-6, further supporting the utility of AA in treating osteolytic diseases.

One of the most promising areas of application might be diabetic nephropathy where AA can alleviate kidney injury. The authors reported that in diabetic rats induced by a high-fat diet and streptozotocin, AA (10–20 mg/kg) exerted beneficial effects by decreasing oxidative stress via stimulating the Nrf2 pathway, increasing antioxidants (SOD (superoxide dismutase), CAT (catalase), GPx (glutathione peroxidase)), and decreasing RAGE (receptor for advanced glycation endproducts) and Keap1 (Kelch-like ECH-associated protein 1) levels. This significant reduction in oxidative stress is likely a result of reduced inflammation (NF-κB, IL-6, TNF-α), fibrosis (TGF-β1 (transforming growth factor beta 1), GSK-3β (glycogen synthase kinase 3 beta)), and apoptosis (caspase-3, Bax) and improvement in parameters of renal function (Wahab et al., 2022) (Table 1).