Ion channels are pivotal targets of BLA in its analgesic mechanism, encompassing voltage-gated sodium channels (VGSCs), transient receptor potential channels (TRP), and calcium channels, among others. These channels are essential for peripheral nociception and central pain transmission. Numerous studies have demonstrated that BLA induces analgesia by modulating these channels, thereby providing significant insights into its molecular mechanism (Figure 2).

BLA, a natural diterpenoid alkaloid, exhibits a unique integrated mode of anti-inflammatory and immunomodulatory actions. This dual regulatory mechanism offers a novel approach for treating inflammatory diseases.

In terms of anti-inflammatory mechanisms, BLA significantly modulates the expression of pro-inflammatory factors. In a mouse model of allergic asthma (Zhan et al., 2019), BLA treatment notably reduced key pro-inflammatory factors, including IL-4, TNF-α, and MCP-1, in the bronchoalveolar lavage fluid. These factors are crucial mediators of allergic inflammatory responses and play a central regulatory role in the pathogenesis of asthma. More importantly, BLA simultaneously inhibits the NF-κB signaling pathway, which is pivotal in immunity, inflammation, and cell proliferation (Liu et al., 2017). This mechanism is significantly important for controlling inflammatory responses.

At the level of immunomodulation, BLA exhibits significant bidirectional regulatory characteristics. Research has demonstrated (Liu et al., 2020) that BLA suppresses airway hyperresponsiveness, pulmonary inflammation, and airway remodeling by restoring the Th1/Th2 balance. In an animal model of allergic asthma (Zhan et al., 2019), BLA not only significantly reduced the levels of total serum IgE and IgG but also decreased the counts of eosinophils, lymphocytes, and macrophages in the bronchoalveolar lavage fluid.

The integrated anti-inflammatory and immunomodulatory effects of BLA hold significant pathophysiological implications. In the context of autoimmune diseases, the overactivation of the immune system results in the release of numerous pro-inflammatory factors and abnormal immune cell functions, leading to tissue damage and chronic inflammation (Song et al., 2024). BLA restores the inflammation-immune balance at the molecular level through a unique dual regulatory mechanism that simultaneously inhibits the production of pro-inflammatory factors and modulates the functional state of immune cells.

Bone repair is a complex biological process that involves the precise coordination of multiple stages, including inflammation regulation, angiogenesis, osteoblast differentiation, and modulation of osteoclast activity (Bahney et al., 2019). Maintaining a balance between osteoblasts and osteoclasts is crucial for effective bone healing (Mi et al., 2022). Recent studies have revealed that BLA exhibits a unique dual regulatory mechanism in promoting bone repair: it not only inhibits excessive osteoclast activity but also optimizes the local tissue microenvironment, thereby creating favorable conditions for the osteogenic process.

Peng et al. (2023) established a mouse model of tibial fracture to validate the promoting effect of BLA on bone repair. The results demonstrated that BLA not only effectively alleviated mechanical and thermal hyperalgesia induced by the fracture, but, more importantly, significantly promoted fracture healing.

In terms of cellular molecular mechanisms, the study by Zhang et al. elucidated the inhibitory effect of BLA on osteoclast differentiation (Zhang et al., 2018). The research demonstrated that BLA inhibits the activation of the NF-κB signaling pathway, thereby obstructing the formation of osteoclasts and the activity of bone resorption. Building upon this foundation, Wang et al. (2024) further illustrated that, in addition to regulating osteoclasts, BLA downregulates the expression of pro-inflammatory factors such as TNF-α, IL-1, and IL-6, while also diminishing the production of prostaglandin E2 (PGE2). This modulation of inflammatory microenvironment at the molecular level occurs during the early stages of fracture.

This multi-target regulatory mechanism holds significant clinical translational value. During the early inflammatory phase of fracture healing, excessive inflammatory responses can delay the healing process and exacerbate pain (ElHawary et al., 2021). BLA precisely regulates the release of inflammatory factors, maintaining the necessary inflammatory response to initiate the repair process while preventing excessive inflammation that could lead to tissue damage. Simultaneously, its selective inhibition of osteoclast activity ensures that bone formation predominates during remodeling. This characteristic endows BLA with broad application prospects in the treatment of orthopedic diseases. More importantly, the bone repair-promoting effect of BLA, coupled with its analgesic properties, offers a novel solution and research direction for addressing the clinical challenge posed by traditional analgesic drugs, such as non-steroidal anti-inflammatory drugs, which may interfere with bone healing (Al Farii et al., 2021) (Table 2).

The cytochrome P450 (CYP450) enzyme system constitutes the core regulatory network for drug metabolism within the body (Klein and Zanger, 2013). By catalyzing oxidation, reduction, and hydrolysis reactions of drugs, it directly influences the blood concentration levels of these substances, thereby affecting their therapeutic efficacy and potential toxic reactions (Miksys and Tyndale, 2009). Among the various subtypes of the CYP450 enzyme system, CYP3A4 assumes a predominant role (Guengerich, 2008). As a structurally complex diterpenoid alkaloid, the metabolic transformation of BLA in the body heavily relies on the catalytic function of the CYP450 enzyme system. Consequently, any factors that influence the activity of CYP450 enzymes, such as drug interactions or environmental factors, may significantly alter the pharmacokinetic characteristics of BLA, thereby impacting the safety and efficacy of its clinical application.

Li et al. (2022) identified that BLA serves as a sensitive substrate and competitive inhibitor of CYP3A4, which may significantly contribute to its clinical adverse reactions. The inhibition of CYP3A4 activity by BLA impacts the metabolic clearance of other drugs, thereby increasing the risk of drug accumulation and toxicity.

Therefore, a comprehensive understanding of the CYP450 metabolic characteristics of BLA and the potential risks of drug interactions, along with the establishment of a personalized medication monitoring system, is crucial for enhancing the safety and efficacy of its clinical application.

The microsphere drug delivery system exhibits significant potential for the local sustained-release administration of BLA. Wang et al. (2024) developed long-acting BLA microspheres (BLA-MS) for intra-articular injection, successfully controlling the initial burst release to an exceptionally low level. This characteristic of low burst release effectively mitigates toxic side effects caused by high local concentrations and significantly extends the drug’s retention time within the joint cavity.

In the collagen-induced arthritis rat model, the localized sustained-release system of BLA-MS establishes a drug reservoir at the lesion site. This approach mitigates the risks of inflammatory damage and infection associated with frequent dosing, thereby significantly enhancing patient compliance.

Liposomes are biocompatible nanocarriers that exhibit excellent properties, including the ability to prolong drug action time through sustained-release mechanisms and to reduce toxic reactions (Allen and Cullis, 2013). More importantly, liposomal technology can facilitate targeted delivery via surface modification, thereby expanding the clinical application possibilities of BLA (Sercombe et al., 2015).

The long-acting local anesthetic bupivacaine (Exparel) provides analgesic effects lasting up to 96 h through the use of liposome technology (Hussain et al., 2021). Consequently, BLA is anticipated to enhance efficacy and improve safety through the application of this technology.

The application of nanocarrier technology has demonstrated revolutionary advantages in enhancing the targeting and bioavailability of BLA. Smart nanocarriers facilitate the selective enrichment of drugs at the lesion site while simultaneously minimizing toxic side effects on normal tissues (Mitchell et al., 2021). Li et al. (2025) developed reactive oxygen species (ROS)-responsive hierarchical targeting micelles (TK-FA-BLA-MS), which construct dual-responsive smart nanocarriers by integrating ROS-sensitive thioketal (TK) units and M1 macrophage-specific targeting groups, such as folic acid (FA).

The immunomodulatory effect achieved through the regulation of macrophage phenotypes unveils a novel mechanism of action for BLA in the treatment of rheumatoid arthritis, transcending its traditional analgesic and anti-inflammatory functions. This effect enhances the uptake efficiency of activated macrophages and promotes their polarization, thereby establishing a groundbreaking mechanism of action for BLA in the management of rheumatoid arthritis (Zhang et al., 2017).

As a C19-type diterpenoid alkaloid, the acetyl ester group at the C-8 position and the benzoyl group at the C-14 position in the molecular structure of BLA are crucial for its pharmacological activity and toxicity. Structure-activity relationship studies (Ameri, 1998) have demonstrated that the ester substitutions at the C-8 and C-14 positions are the primary pharmacophores influencing its sodium ion channel binding activity. Modifications at these two sites directly impact the strength of the drug’s interaction with voltage-gated sodium ion channels (VGSCs), thereby determining the balance between its analgesic effects and neurotoxicity (Wang et al., 2010).

The presence of the C-8 acetyl ester group significantly enhances the compound’s affinity for sodium ion channels (Ameri, 1998), a structural feature that plays a dominant role in the toxic manifestations of aconitine-type alkaloids. Hydrolysis or substitution of the acetyl group at the C-8 position markedly reduces the acute toxicity of the compound; however, this alteration also weakens its analgesic activity (Li et al., 2016). In contrast, modifications to the C-14 benzoyl group exhibit a more complex influence on toxicity. Research indicates (Zhao et al., 2024) that the removal or substitution of the benzoyl group at the C-14 position can diminish neurotoxicity to some extent while preserving partial analgesic activity, thus providing a potential pathway for achieving a separation between toxicity and efficacy.

Moreover, a synergistic effect exists between the substituents at the C-8 and C-14 positions. When ester groups are present at both locations simultaneously, the compound demonstrates the strongest sodium channel blocking activity, albeit with a concomitant increase in toxicity risk (Bello‐Ramírez and Nava‐Ocampo, 2004). This discovery of the structure-activity-toxicity relationship has established a theoretical foundation for subsequent directed structural optimization (Table 3).

In recent years, researchers have synthesized a series of BLA derivatives through structural modifications, aiming to reduce toxicity while maintaining or enhancing analgesic activity.

With the advancement of computational chemistry and artificial intelligence technologies, quantitative structure-activity relationship (QSAR) analysis, along with molecular docking techniques based on the BLA molecular structure, has provided theoretical guidance for research on the separation of toxicity and efficacy.

The BLA QSAR study has established a quantitative relationship between its structural characteristics and toxicity. Koleva et al. demonstrated that compounds possessing an aroyl/aroyloxy group at the C-14 position (such as BLA and aconitine) exhibit greater toxicity compared to those with an aroyloxy group at the C-4 position (Bello‐Ramírez and Nava‐Ocampo, 2004). Moreover, machine learning algorithms can develop QSAR models based on features such as molecular weight and partition coefficient, facilitating accurate predictions of BLA’s cardiac and neurotoxicity (Shah et al., 2024).

Furthermore, molecular docking technology can be employed to predict the binding modes and affinities of BLA and its derivatives with voltage-gated sodium ion channels. This approach enables the evaluation of the effects of C-8 acetyl ester and C-14 benzoyl modifications on the strength of protein-ligand binding.

By integrating various methods such as QSAR, molecular dynamics simulations, and free energy calculations (Turabekova et al., 2008), this study aims to provide systematic guidance for the separation of toxicity and efficacy in biological ligand activity (BLA) and to facilitate rational drug design.

Biologics, as traditional natural products, face numerous challenges in modern clinical applications; however, technological innovations have opened broad prospects for their future development. Artificial intelligence is revolutionizing drug development models by employing machine learning algorithms to predict toxicity profiles and optimize compound structures, thereby providing new approaches for developing safer biologic derivatives (Fu and Chen, 2025). The intelligent design of novel drug delivery systems facilitates the precise development of targeted drug delivery and controlled-release formulations, which hold promise for addressing the bioavailability and targeting issues associated with biologics (Serrano et al., 2024).

The synergistic development of these technological innovations will facilitate the transformation of BLA from traditional analgesic drugs to individualized precision medicine, thereby playing a more significant role in the field of pain medicine.

BLA has received approval in China for the treatment of chronic pain and rheumatoid arthritis (Xie et al., 2018b). Recent clinical and basic research has further substantiated its traditional indications.

In the treatment of neuropathic pain, clinical studies have demonstrated that BLA can effectively alleviate human neuropathic pain (Wang et al., 2007). Furthermore, BLA has been shown to mitigate paclitaxel-induced neuropathic pain (Zhu et al., 2015).

In the treatment of arthritis, BLA demonstrates anti-inflammatory and analgesic effects by decreasing the expression of prostaglandin E2 (PGE2). Recent studies have developed long-acting BLA microspheres, which offer multidimensional therapy for rheumatoid arthritis via intra-articular administration, thereby showcasing their potential for localized drug delivery (Wang et al., 2024).

In the context of cancer pain, BLA has been shown to effectively inhibit both peripheral and central sensitization associated with chronic pain; however, it does not exert any influence on acute pain (Xie et al., 2018b).

In summary, BLA does not induce tolerance or addiction in the treatment of chronic pain. However, to further optimize its application in traditional indications, it is necessary to conduct more high-quality randomized controlled trials to verify its long-term efficacy and safety, as well as to establish standardized dosing regimens and monitoring indicators (Li et al., 2022).

Current clinical guidelines for pain management increasingly emphasize the significance of multimodal analgesia. This approach minimizes adverse effects by employing medications with diverse mechanisms of action. A notable advantage of combining BLA in therapy is its capacity to diminish opioid tolerance. Research indicates (Mai et al., 2020) that BLA’s unique analgesic mechanism, which operates independently of opioid receptors, not only delivers effective pain relief but also mitigates opioid tolerance and dependence. This offers new avenues for developing safer and more effective pain management strategies (Zhu et al., 2015) (Table 7).