Pyrolysis is one of the most extensively studied and commercially applied techniques for lignin depolymerization. It refers to the heat treatment of lignin at relatively high temperatures under anoxic conditions, with or without catalysts (Agarwal et al., 2018). A temperature of 400°C is usually regarded as the critical point of lignin pyrolysis. Primary pyrolysis takes place at the temperature ranging from 200°C to 400°C. At this stage, ether cleavage, especially α-O-4 and β-O-4, accounts for most of the reactions. When the temperature is above 400°C (secondary pyrolysis), radical reactions become predominant and therefore result in an extensive rearrangement of the lignin structure. In this temperature range, C-C bonds cleavage occurs and leads to the formation of oligomers as well as monomers. Nevertheless, undesirable re-polymerization is also promoted under harsh reaction conditions, which is the main issue associated with thermal processing development (Li and Takkellapati, 2018).

By different heating rates and residence time, pyrolysis can be classified into conventional (or slow) pyrolysis and flash (or fast) pyrolysis (Laurichesse and Avérous, 2014). Concerning conventional pyrolysis, lignin is slowly heated to approximately 500°C with a relatively long residence time ranging from 5 to 30 min (Figueiredo et al., 2018). On the contrary, flash pyrolysis takes place at high temperatures between 600°C and 1,000°C with a much shorter residence time (0.5–5 s) (Figueiredo et al., 2018). The main product derived from conventional pyrolysis is a gaseous phase (syngas), while the flash pyrolysis technique is predominantly used to produce bio-oil, accounting for 60–75 wt% of the end products (Hoang et al., 2021). The mixture of end products from lignin pyrolysis includes monomeric and oligomeric phenols in liquid oil (e.g., phenol, catechol, syringol, and guaiacol), volatile products (e.g., methanol and acetone), gaseous compounds (e.g., H₂, CO₂, CH_4, and C₂H₄) as well as biochar (Liu et al., 2015; Hoang et al., 2021). The yield and distribution of products are dependent on different sources of lignin and processing conditions (e.g., pyrolysis temperature, reactor type/heating rate, residence time, and feeding rate) (Fan et al., 2017; Figueiredo et al., 2018).

Hydrothermal liquefaction (HTL) is another baseline technology of lignin depolymerization which has been extensively explored in recent years. Different from other thermal depolymerization techniques such as pyrolysis and gasification, HTL is a better candidate for biomass with high water content because there is no need for preliminary drying processes, which are both energy-intensive and costly (Kumar et al., 2017b). It is usually applied to obtain low-oxygen liquid bio-oil and/or phenolics (e.g., syringol, vanillin, guaiacol, as well as phenolic trimers to oligomers) (Cao et al., 2020) from lignin at high pressure (5–28 MPa) and relatively moderate temperature (200–400°C) in a solvent with or without catalysts (Kang et al., 2013). In many cases, HTL of lignin is carried out in hot-compressed water (Li and Takkellapati, 2018). Subcritical water (≤374°C and 22 MPa) behaves differently from water at room temperature and supercritical water (≥374°C and 22 MPa), and it has a few unique properties such as low viscosity and high solubility of organic compounds, making it a suitable reaction medium for biomass conversion. In other words, water serves not only as a green solvent but also as one of the reactants and catalysts in the lignin HTL process (Yang et al., 2020). Therefore, HTL is regarded as a sustainable and environmentally friendly technique for lignin depolymerization with less secondary pollution as well as a high conversion rate (Cao et al., 2018).

Many attempts have been made to investigate the depolymerization mechanism of lignin via HTL for the production of value-added aromatic derivatives. Hydrolysis of lignin into methoxy phenolics usually occurs first, followed by further hydrolysis of phenolics because ether bonds breakage requires less energy than C-C bonds (Singh et al., 2014). Cao et al. (2018) divided HTL of lignin depolymerization into three steps, including lignin hydrolysis, cleavage of ether bonds and C-C bonds among monomers, and the degradation of methoxy groups on benzene ring as well as the alkylation of functional groups on the benzene ring. In terms of critical parameters, the yield and distribution of products derived from lignin HTL are strongly dependent on temperature and reaction time while less dependent on other reaction parameters such as pressure and stirring speed of the reactor (Cao et al., 2018). It is reported that depolymerization of lignin and re-polymerization of intermediate products will be promoted simultaneously with the increase of temperature, leading to increases in both low-molecular-weight compounds and solid residue (Singh et al., 2014). Reaction time is an important parameter of lignin HTL that decides the nature of the end products. Long reaction times can increase the composition of low molecular end products by lignin HTL, with further prolonged reaction times inducing condensation of low molecular products into coke (Xu and Li, 2021). The heating rate is also identified as an important factor because the HTL process is kinetically controlled (Li and Takkellapati, 2018).

Catalysis has been regarded as an indispensable technique in the lignin conversion process. The main advantages of catalytic lignin depolymerization are to accelerate the conversion and suppress the formation of undesirable products (e.g., char) while keeping the reaction conditions relatively mild. On the other hand, catalysts are also used to promote selective bond cleavage and therefore lead to the generation of specific value-added compounds or increase the ratio of desirable downstream products (Zhang and Wang, 2020).

Base-catalyzed depolymerization (BCD) of lignin is generally carried out under relatively harsh conditions (at the temperature above 300°C and high pressure over 200 bar), from which the most abundant products include catechol, syringol, and their derivatives (Wang et al., 2013; Xu et al., 2014). The basic mechanisms of BCD are the breakage of the aryl-alkyl bond (especially β-O-4 bond), which usually requires a temperature higher than 270°C as well as the cleavage of functional groups (e.g., methoxy groups) attached to the aromatic rings (Wang et al., 2013; Xu et al., 2014). Toledano et al. (2012) conducted experiments on BCD of organosolv lignin (olive tree) for phenolic monomer production by using different base catalysts, including KOH, NaOH, Ca(OH)₂, LiOH, and K₂CO₃. The results suggested that base catalysts are capable of suppressing lignin re-polymerization and char formation. In addition, it was observed that stronger bases, especially NaOH was able to produce more lignin-derived bio-oil than weaker bases such as LiOH (Toledano et al., 2012). Among a variety of different homogeneous base catalysts, NaOH, KOH, and Na₂CO₃ were the most extensively implemented in BCD reactions by researchers (Mahmood et al., 2013; Wang et al., 2013; Ahmad et al., 2018). It was reported that the formation of lignin-derived monomers was proportional to the concentration of NaOH in an aqueous solution (Roberts et al., 2011).

The harsh conditions required for BCD of lignin bring difficulties to product selectivity control and product purification, making acid-catalyzed lignin hydrolysis under mild conditions a better option for value-added chemical production (Xu et al., 2014). Similar to the BCD of lignin, acid-catalyzed lignin depolymerization also aims at the cleavage of β-O-4 bonds (Wang et al., 2013). The catalytic effects of different types of acids, including HCl, H₂SO₄, H₃PO_4, and formic acid (FA), were investigated by Tayier and colleagues under mild microwave-assisted heating at the temperature of 160°C. FA and H₂SO₄ were identified as decent catalysts for lignin depolymerization resulting in lower M_w compounds and less solid residue in the product streams, while H₃PO₄ facilitated unfavorable re-polymerization (Tayier et al., 2017). More than 60wt% yield of low-molecular-mass aromatics was reported by Rahimi et al. (2014), who carried out depolymerization of oxidized lignin under mild conditions in aqueous FA.

Oxidative depolymerization or oxidation is a promising possibility to expand the use of lignin due to the abundant hydroxyl groups in the lignin structure. Novel approaches in oxidative depolymerization of lignin are exploring the ability to conduct the depolymerization process under ambient conditions in cost-effective means (Ahmed et al., 2021). It is usually applied to produce phenolic derivatives by using oxidants that help to preserve the lignin aromatic rings, such as hydrogen peroxide, nitrobenzene, metallic oxide, and oxygen (Laurichesse and Avérous, 2014; Figueiredo et al., 2018). The reaction is usually associated with electron transfer or hydrogen atom extraction from lignin, resulting in a wide range of follow-up reactions such as hydroxylation of aromatic rings, phenol oxidation, benzylic oxidation, ring-opening reactions, and demethylation (Li and Takkellapati, 2018). The main products derived from oxidative depolymerization of lignin include aromatic aldehydes (e.g., vanillin and syringaldehyde) and their corresponding acids (e.g., vanillic acid and syringic acid) (Vangeel et al., 2018). Kraft lignin with high C-C content is a suitable candidate for oxidative depolymerization because this technique is very effective in breaking C-C bonds (e.g., 5–5′ and α-5’) (Li and Takkellapati, 2018).

The reaction mechanism, product yield, and product distribution of lignin oxidation strongly depend on processing conditions, especially pH and oxidant selection. Many attempts have been made to investigate the oxidative depolymerization of lignin by hydrogen peroxide in both acidic and alkaline conditions. Xiang and Lee (2000) found that oxidative depolymerization of precipitated hardwood lignin (PHL) requires lower temperatures (80–90°C) under strongly alkaline conditions while higher temperatures (130–160°C) under acidic conditions to achieve the same degree of depolymerization (around 98wt%). It is also worth noticing that formic acids, oxalic acids, and acetic acids are predominant components of product streams while only trace amounts of vanillin and syringaldehyde were detected, meaning that hydrogen peroxide may not be preferred if the desired product is aromatic aldehyde and corresponding acids (Xiang and Lee, 2000). Compared to hydrogen peroxide, nitrobenzene is considered a more effective oxidant to produce aldehydes (e.g., vanillin, syringaldehyde, and p-hydroxybenzaldehyde) and their respective acids (e.g., vanillic acid, syringic acid, and p-hydroxybenzoic acid) (Min et al., 2015). Min et al. (2015) also suggested that the maximum yield of a product derived from softwood and hardwood lignin by alkaline nitrobenzene oxidation could be achieved at a temperature of 170°C and a residence time of 2.5 h. Sometimes metallic oxides and transition metals are used as alternative oxidants due to the carcinogenicity of nitrobenzene (Figueiredo et al., 2018).

Ionic liquids (ILs) are defined as substances composed of organic cations and inorganic/organic anions, which are in the liquid phase at or below 100°C (Xue et al., 2016). ILs have aroused much attention and were taken into considerations of lignin depolymerization in recent years due to their special properties. For instance, ILs have high potential in dissolving a wide range of biomass compared to other solvents, contributing to better utilization of bioresources (Hossain and Aldous, 2012). Although the dissolution mechanism of lignin in solvents remains unclear, a recent study showed that lignin dissolution by ILs is a function of a proton donating and accepting the ability of ILs (Akiba et al., 2017). Additionally, ILs exhibit extremely low vapor pressure due to their ionic nature, leading to the minimized release of volatile organic compounds (VOCs) (Dai et al., 2016; Zhu et al., 2018). On the other hand, the properties of IL (e.g., acidity, the solubility of catalyst, miscibility with solvents, and melting point) can be adjusted by a specific combination of cations and anions, making it a “designer solvent and/or catalyst” that is tailored to different reactions and processes (Cox et al., 2011; Zhu et al., 2018). IL is also well-known for its high thermal stability, recyclability, and non-flammability (Dai et al., 2016; Gillet et al., 2017).

Designs of efficient lignin depolymerization strategies should be based on a profound understanding of the properties of different ILs and the roles that various cations and anions play in the conversion process. It is reported that alkylsulfonate anions are most effective with respect to reducing the polydispersity or molecular weight and promoting the reaction activity of lignin, followed by lactates, acetates, chlorides, and phosphates (George et al., 2011). Targeted cleavage of β-O-4 linkages in lignin structure for guaiacol production has been extensively explored in the past several years, and the yield of breakage product in several ILs was found to follow the order [Hmim]Cl > [Bmim][HSO₄] > [Hmim]Br > [Hmim][HSO₄] > [Hmim][BF₄] (Cox et al., 2011). Binder et al. (2009) found that weakly basic anions (e.g., [BF4]^-, [CF3SO3]^- and [PF6]^-) facilitated dealkylation while moderately basic anions (e.g., Cl⁻, Br⁻ and [CF₃CO₂]^-) inhibited the unfavorable dealkylation reaction in targeted cleavage of ether bonds in lignin structure catalyzed by Brønsted acid (Binder et al., 2009).

The high cost of ILs severely limits the industrialized lignin depolymerization, which makes the recycling or reuse of ILs extremely important. In addition, product separation from ILs is necessitated by industrial chemical purification and reaction product analysis (Zakzeski et al., 2010). However, it’s complicated to separate ILs with lignin-derived products without using organic solvents due to strong π-π interactions between aromatic lignin structure and ILs (Hossain and Aldous, 2012; Wang et al., 2013). The currently available technologies applied to analyze dissolved lignin-derived products in ILs include ultraviolet-visible (UV-vis) and infrared spectroscopy, mass spectrometry, light scattering techniques, and nuclear magnetic resonance (NMR) spectroscopy (Zakzeski et al., 2010). For the future application of ILs in lignin depolymerization, the ability to scale up, toxicity, and life-cycle analysis should also be taken into considerations (Stark, 2010; Weldemhret et al., 2020).

Among various aromatic monomers generated from lignin depolymerization, vanillin has been commercialized with an annual production of around 3,000 tons (Fache et al., 2016; Li and Takkellapati, 2018). Although the production of other bio-based aromatics from lignin depolymerization has been intensely investigated, technology maturity is still relatively low (Lange et al., 2013). Vanillin (3-methoxy-4-hydroxybenzaldehyde) is one of the most widely used flavoring agents extracted from dried vanilla beans. As a plant secondary metabolite, isolated vanillin is a white to light yellow crystalline powder with a sweet and creamy vanilla-like odor (Priefert et al., 2001; Bezerra et al., 2016). Besides natural vanilla beans (<1%) as a major source of commercial vanillin market, petroleum-based chemicals (roughly 85%) and lignin (approximately 15%) are two other important sources of synthetic/nature-identical vanillin (Agrawal et al., 2014; Fache et al., 2016). Considering the environmental sustainability and economic relevance, lignin is identified as a promising source of vanillin production compared to the other two sources. In the global market, about 60% of the industrial vanillin is used as a food additive, while the remaining 40% is used as cosmetic ingredients (approximately 33%) and pharmaceuticals (roughly 7%) (Bajpai, 2018).

In food industries, vanillin is widely found in sweet foods and beverages, especially ice cream, chocolate, confections, and baked goods (e.g., cakes and biscuits). Aside from the application in human foods, vanillin is used as a feed additive for poultry (e.g., chicken and turkey), cattle, and pigs, which provides desirable olfactive notes and promotes animal fattening (Mohammadi and Kim, 2018). On the other hand, vanillin is extensively used to produce other flavoring agents such as jasmine oil and zingiberene (ginger flavoring agent) (Banerjee and Chattopadhyay, 2018). Since vanillin exerts antioxidant and anti-microbial properties, it’s used as a food preservative as well (Rupasinghe et al., 2006; Banerjee and Chattopadhyay, 2018). In the fragrance industry, vanillin is a common component of body lotions, shampoos, shower gels, soaps, room sprays, air fresheners, and candles.

Nowadays, the application of vanillin has been dramatically shifted from a flavoring and fragrance ingredient to an important intermediate/precursor for the synthesis of pharmaceuticals (e.g., l-dopa, dopamine, Aldomet, papaverine, and ftivazide), bio-based polymers (e.g., thermoset and thermoplastic polymers) and fine chemicals (Fache et al., 2016; Tarabanko and Tarabanko, 2017). In the pharmaceutical industry, vanillin is usually used as a masking agent to mask the unpleasant flavor of pharmaceutical drugs (Van Wyk and Wink, 2014). It is also used to synthesize several pharmaceutical chemicals, including cyclovalone used as a digestant or choleretic, etamivan (ethamivan) as a stimulant for the nervous and respiratory system, levodopa (l-dopa) as an anti-Parkinson’s disease agent, dopamine with anti-hypotensive effect, Aldomet (methyldopa) with anti-hypertensive effect, papaverine as a vasodilator and ftivazide for tuberculosis treatment (Bjørsvik and Liguori, 2002; Tarabanko and Tarabanko, 2017). Furthermore, the potential health-beneficial effects of vanillin itself have been reported by many researchers. For example, Tai et al., evaluated the antioxidant activity of vanillin by using multiple antioxidant assays and the experimental results indicated that vanillin exhibited a potent antioxidant effect in 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) radical cation/ABTS ^·+ scavenging assay, oxygen radical absorbance capacity (ORAC) assay and oxidative hemolysis inhibition assay (OxHLIA) (Tai et al., 2011). It is widely believed that the presence of the hydroxyl group attached to an aromatic ring contributes to the antioxidant effect of vanillin (Bezerra et al., 2016). Rupasinghe et al. (2006) reported that vanillin effectively inhibited the growth of selected pathogenic, indicator, and spoilage microorganisms in vitro on fresh-cut apple slices, suggesting that vanillin could be a potential antimicrobial agent for refrigerated fruits and vegetables (Rupasinghe et al., 2006). A similar result was described by Rojas-Graü et al. (2007), who found that vanillin-containing coatings exhibited strong anti-microbial activity and prolonged the shelf-life of fresh-cut ‘Fuji’ apples (Rojas-Graü et al., 2007). In past studies, the antimutagenic activity of vanillin and vanillin derivatives has been assessed in different cell models (in vitro) and animal models (in vivo) with the presence or absence of chemical and physical mutagenic agents (Li et al., 2019; Ma et al., 2019; Sefi et al., 2019; Ghanim et al., 2021). Most of these studies indicate that vanillin is a pharmacological candidate to alleviate mutagenicity-associated diseases, especially cancers. The development of vanillin derivatives coupled with metals (e.g., Ni and Co.) as cancer therapeutics is one of the growing research interests (Kumar et al., 2017a; Kumar et al., 2021; Bahron et al., 2019).

Together with other lignin derivatives such as ferulic acid, guaiacol, syringaldehyde, and 4-hydroxybenzoic acid, vanillin (Figure 5A) is intensively investigated as a bio-based building block, and many efforts have been made by the scientific community to prepare a wide range of polymer products in recent years (Fache et al., 2015; Fache et al., 2016; Llevot et al., 2016). The hydroxyl and aldehyde reactive sites of vanillin structure provide opportunities for chemical modification to produce different monomers, which can be subsequently polymerized into value-added materials with diverse thermal and physical properties (Zhang et al., 2015). Characterized by rigid aromatic structures, vanillin and its derivatives (e.g., vanillic acid and vanillyl alcohol) are perfect candidates for the preparation of high-performance thermosetting materials, especially epoxy polymers, in which epoxy monomers with an aromatic structure bring stability to the network (Fache et al., 2015). The generated epoxy polymer can be employed in a broad spectrum of industrial fields such as construction, automotive, and aerospace with diverse applications such as adhesives and binders, paints and coatings, composites, electrical/electronic laminates, as well as flooring and paving (Auvergne et al., 2014). Vanillin and its derivatives are also high potentials for thermoplastics production, requiring aromatic monomers, especially polyesters with good thermal properties (Harvey et al., 2015). Apart from epoxy polymers and polyesters, other bio-based polymers generated from vanillin include phenolic resins, (meth)acrylic polymers, polyacetal, polyaldimines and polybenzoxazines, polymers from alkenes as well as polymers from the reductive coupling of aldehydes (Fache et al., 2015). These polymers can be further applied in insulators, furniture, packaging, containers, foams, etc. (Sun et al., 2018).

Syringaldehyde (3,5-dimethoxy-4-hydroxybenzaldehyde) is another aromatic aldehyde of interest generated from lignin depolymerization. Similar to vanillin, syringaldehyde is used as an ingredient in the flavor and fragrance industry as well. Although syringaldehyde is far less commercialized as vanillin, it has become an emerging lignin-derived chemical, especially after the discovery of its role as an essential precursor of several pharmaceutical drugs used for the treatment of bacterial infection such as trimethoprim (3,4,5-trimethoxybenzaldehyde), Bactrim, and Biseptal (sulfamethoxazole or trimethoprim) (Tarabanko and Tarabanko, 2017; Ibrahim et al., 2012). Vanillin is also a precursor of trimethoprim synthesis, but syringaldehyde has the advantage of having two methoxyl groups (Figure 5B) (Mota et al., 2015). At the current stage, only preliminary in vitro tests have been carried out to identify the bioactive properties of syringaldehyde. Nevertheless, these valuable “cornerstones” are helpful for the identification of new potential research areas and the expanding application of syringaldehyde. For instance, Bountagkidou et al. (2010) found that syringaldehyde possesses exceptionally high antioxidant activity (peroxyl radical scavenging) compared to vanillin and protocatechuic aldehyde in crocin bleaching assay, which is an in vitro antioxidant assay. Syringaldehyde also exhibits anti-microbial activity against bacteria and fungi. It’s reported that paper hand-sheets from pulps treated with monophenols such as syringaldehyde and acetosyringaldehyde exerted antibacterial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumonia, which can cause a wide range of human diseases (Fillat et al., 2012). González-Sarrías et al. (2012) evaluated the anti-cancer effect of 51 types of purified phenolic constituents isolated from Canadian maple syrup extract. The experimental results indicated that syringaldehyde and seven other phenolic compounds exhibited higher potential in suppressing the proliferation of colon cancer cells. These bioactive properties and potential health-beneficial effects suggested that syringaldehyde could be further examined as a food additive, natural health product (NHP), or pharmaceutical.

Ferulic acid (FA, 4-hydroxy-3-methoxycinnamic acid, Figure 5C), belonging to the family of hydroxycinnamates, is also a common product of great value generated from lignin depolymerization. As a derivative of caffeic acid, FA is very abundant in fruits, vegetables, and beverages such as coffee and beer (Mancuso and Santangelo, 2014). Furthermore, it is an effective component of Chinese medicine herbs such as Cimicifuga heracleifolia (Shengma), Lignsticum (Chuanxiong/Chinese lovage), and Angelica sinensis (Dong Quai/female ginseng) (Ou and Kwok, 2004). FA is also an important precursor of industrialized vanillin production (Kumar and Pruthi, 2014).

The methoxy, hydroxyl, and carboxylic acid groups on the benzene ring of FA (Figure 5C) provide opportunities for stabilization of phenoxyl radical intermediate and even termination of free radical chain reactions while reacting against a free radical (Ghosh et al., 2017). These functional groups make FA an efficient scavenger of both reactive oxygen species (ROS) and reactive nitrogen species (RNS) (Mancuso and Santangelo, 2014). In the food industry, FA can be used as a preservative due to its potent antioxidant property. The first use of FA as a food preservative to preserve orange and linseed oil was reported by a Japanese research team (Tsuchiya and Takasawa, 1975). Moreover, FA is an inhibitor of food discoloration that helps to prevent a color change of green tea and banana due to oxidation (Kumar and Pruthi, 2014). Since FA is a strong UV absorber and can be easily absorbed by the skin at acidic and neutral pH, another application of FA is a cosmetic ingredient.

Besides its application as a food additive and cosmetic ingredient, FA is identified as an anti-diabetic agent, an anti-cancer agent, a neuroprotective agent, as well as a cardiovascular agent, considering its potential in the area of human health (Parmar et al., 2015). It has been widely reported that FA effectively reduced the blood glucose level or alleviated the physical symptoms of diabetes (e.g., fattening) in induced diabetic animals (Sri Balasubashini et al., 2003; Ramar et al., 2012; Song et al., 2014). The main factors associated with cancer pathogenesis include enhanced cell proliferation, chronic inflammation, abnormal activation of pro-inflammatory pathways, free radical formation, and resulted in oxidative damage (Mancuso and Santangelo, 2014). In light of this, the ability of FA to scavenge free radicals, suppress cell proliferation, and activate cytoprotective enzymes in either in vitro or in vivo assays suggests that FA has the potential to play an adjuvant role in cancer therapy (Menter et al., 2010; Karthikeyan et al., 2011; Fahrioglu et al., 2016). Due to the discovery of anti-hypertensive and antihyperlipidemic properties by animal models, FA has its potential clinical use in cardiovascular diseases as well (Bumrungpert et al., 2018; Alam, 2019).

Lignophenols (LPs) are lignin-derived macromolecules produced experimentally from raw biomass by phase-separation systems, in which cellulose and hemicellulose of lignocellulosic are converted into hydrolyzed carbohydrates while lignin is converted into LPs (Sato et al., 2006; Lochab et al., 2014). Under hydrothermal conditions, these lignin-based polymers can be further converted into monophenols (e.g., phenol, catechol, syringol, and cresol) (Lochab et al., 2014). LPs are characterized by their high phenolic contents as well as high stabilities, and they exert a series of pharmacological activities (e.g., radical scavenging, neuroprotection, and diabetes control) (Lochab et al., 2014). Akao et al. (2004) examined the effects of various LPs isolated from bamboo lignin and reported that lignocresol, named lig-8, was a highly effective neuroprotector that prevented human neuroblastoma cells (SHSY-5Y) from abnormal apoptosis induced by hydrogen peroxide (H₂O₂) and therefore delayed the progression of neurodegenerative diseases. The experimental results suggested that the neuroprotective effects of lig-8 could be attributed to the scavenging of reactive oxygen species (ROS) and blocking of caspase activation, which was identified as an apoptosis executioner (Akao et al., 2004; Ito et al., 2007). Moreover, lig-8 exhibited an anti-apoptotic effect by suppressing H₂O₂-induced dissipation of the mitochondrial membrane permeability transition (Akao et al., 2004). Similar results were obtained by many other researchers. Sato et al. (2006) found that LPs had an anti-apoptotic effect on pheochromocytoma (PC12) cells treated with an excessive amount of Cu and Zn, which were highly associated with ROS generation and oxidative cell injury.

In terms of diabetes control, it’s reported that LPs from beech tree (Fagus crenata Blume) played an active role in attenuating oxidative stress and inflammatory damage, activating macrophages as well as promoting glomerular expansion in the kidneys of streptozotocin (STZ)-induced diabetic rats (Sato et al., 2009). LPs-containing diets were proved to be very helpful for lowering plasma triglyceride levels in rats fed a high-fat diet by potentially suppressing the expression of sterol regulatory element-binding protein (SREBP) and acetyl-CoA carboxylase (ACC) (Sato et al., 2012). Mukai et al. (2011) also investigated the effects of lignin-derived LPs on diabetic rats, and their findings suggested that LPs alleviated vascular oxidative stress by inhibiting the expression of nicotinamide adenine dinucleotide (phosphate) (NAD(p)H) oxidase. Apart from the potential in diabetes control, Suzuki et al. (1990) found that LPs extracted from Lentinus edodes (an edible mushroom) have potent antiviral activity against human immunodeficiency virus (HIV) on the basis of the assay for the proliferation of mouse bone marrow cells. Although some health-beneficial effects of LPs have been demonstrated either in vitro or in vivo, their underlying physiological mechanisms remain unclear (Ito et al., 2006; Ito et al., 2007).

Lignin is rarely isolated as 100% purified materials and it is more or less associated with carbohydrate linkages (Zhao et al., 2020). Lignin-carbohydrate complexes (LCCs) are major cell wall components formed by the dehydrogenation of three monolignols, as mentioned in the first section (Sakagami et al., 2010). Within plant biomass, more than 50% of lignin is linked to carbohydrates by covalent bonds, which severely restricts the separation of them in pulping and paper industry, as well as the efficient hydrolysis of raw lignocellulosic biomass for bioethanol production (You et al., 2015). Nevertheless, it’s believed that this small amount of “impurity” (roughly 2–8% by weight) plays a critical role in the reactivity and properties of the macromolecule (Singh et al., 2005). Considering the potential health-beneficial effects of LCC, it displays diverse pharmacological activities as a macromolecular derivative of lignin, including anti-herpes activity, anti-HIV activity, anti-UV activity as well as anti-microbial activity.

Zhang et al. (2007) found that LCC prepared from Prunella vulgaris with a molecular weight of 8,500 exhibited in vivo anti-herpes activity by suppressing viral binding and penetration based on viral binding assay and penetration assay (Zhang et al., 2007). Similar results were also reported by Lee et al. (2011) that LCC derived from Prunella vulgaris exerted anti-viral activity against herpes simplex virus, human cytomegalovirus (HCMV), and measles virus. These results suggested that Prunella vulgaris-derived LCCs possessed potency as a functional ingredient against infectious diseases. As reported by Sakagami et al. (2011), LCC obtained from cacao (Thobroma cacao L.) mass, and cacao husk presented anti-HIV activity, indicating that LCCs could be further exploited as functional food ingredients with immunomodulatory and antiviral effects. The prominent anti-UV activity of LCCs extracted from Sasa senanensis Rehder leaves and Lentinus edodes Mycelia were also well documented, suggesting LCCs could be included in Sun care products (Nanbu et al., 2011; Nanbu et al., 2013; Sakagami et al., 2016). Similar to other phenolic lignin fragments, LCC shows antifungal and antibacterial properties. For instance, Oh-Hara et al. (1990) found that LCC obtained from Pinus parviflora (Pine cones) exhibited anti-microbial activities against a series of microorganisms (e.g., Staphylococcal aureus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Candida albicans, and Salmonella enteritidis) and protected mice from the lethal effects of microbial infection. Moreover, recent studies suggest that LCC can be effective against viruses. LCC isolated from beech wood through microwave acidolysis is effective against encephalomyocarditis virus. Decoupling of carbohydrate moieties from these LCC significantly suppresses the antiviral activity, emphasizing the importance of carbohydrate moieties on LCC for biological activities (Li et al., 2021).