Fucoxanthin in microalgae often binds to chlorophyll to form a fucoxanthin chlorophyll a/c protein complex (FCP), which can respond quickly to changes in the light environment (Xia et al., 2013). While fucoxanthin can be chemically synthesized, it is more efficient to extract it from microalgae. Compared with plants, microalgae grow quickly, often doubling their number per hour. Their productivity is measured in days, whereas plants often take months or years to produce. Microalgae isolated from nature are small and easily viable, making them suitable for cultivation in closed systems in laboratories or factories. There do not require arable land and are unaffected by seasonal climate and the marine environment. Moreover, the high fucoxanthin content of microalgae, the relative ease of the extraction and preparation process compared to macroalgae, and the variery of strain sources make microalgae an ideal cellular factory for the sustainable, large-scale production of fucoxanthin.

The biosynthesis of fucoxanthin was studied using Phaeodactylum tricornutum as a common model species, with high photosynthetic efficiency ( Figure 3 ). The process begins with the generation of isopentenyl pyrophosphate (IPP) through the mevalonate pathway, which is the rate-limiting step in the synthesis of β-carotene. Geranylgeranyl diphosphate (GGPP) is produced by IPP under the action of geranyl pyrophosphate synthase (GGPS) (Xia et al., 2013). Subsequently, octahedron lycopene synthase (PSY) enzyme converts GGPP to produce the first carotenoid, phytoene (Kadono et al., 2015). Phytoene undergoes continuous dehydrogenation by octahydron lycopene desaturase (PDS), ζ-carotene desaturase (ZDS), carotenoid isomerase (CRTISO), resulting in the formation of lycopene (Kadono et al., 2015). Lycopene can produce α-carotene or further forms β-carotene from γ-carotene. Under the action of β-carotene hydroxylase (BCH), β-carotene generates zeaxanthin. Zeaxanthin epoxidase (ZEP) cyclizes zeaxanthin to form violaxanthin through two-step catalysis (Coesel et al., 2008). Ultimately, fucoxanthin can be synthesized from Diadinoxanthin (Lohr and Wilhelm, 1999) or also from Neoxanthin (Kadono et al., 2015). There are two hypothetical pathways for fucoxanthin synthesis, Figure 3 . These are the currently known pathway for fucoxanthin synthesis.

Clarifying of the pathway of fucoxanthin synthes is also important for biomolecular experiments and molecular level studies. It is evidant that the enzymes involved in key synthetic pathways are not yet known and fuether research is needed to investigate potential branching pathways for synthesis.

In the field of research and development of microalgae resources, one of the key problems that must be solved is the screening and breeding of excellent algal strains. Most of the microalgae cultured in current times are isolated directly from the natural environment. They are wild-type algae, which have single traits and poor adaptability to the environment. As a result, they are prone to trait degradation and are not suitable for industrial production and conditions (Benemann, 2013). Natural selection, is time-consuming and laborious. Hence, there is a need for effective breeding methods. Mutagenic breeding, an ideal method for microalgal breeding, is outstanding and easy to operate. Researchers screened a mutant of Phaeodactylum tricornutum using a fluorescence-based high-throughput method (Yi et al., 2018). The mutant showed a 69.3% increase in fucoxanthin compared to wild type, making it an industrially useful fucoxanthin-producing algal strain. UV mutagenesis is also an effective breeding strategy. Yi et al. used stress mutagenesis induced by UV light to enhance the accumulation of fucoxanthin in Phaeodactylum tricornutum and produced mutant strains with improved growth rates (Yi et al., 2015). Furthermore, mutagenesis has the advantage of not being classified as a method producing genetically modified organisms, which exempts it from regulatory issues in many places such as the EU (Tillich et al., 2012). However, there are curenthly challenges in microalgae mutation breeding. Such as obtaining ideal mutant strains, optimizing mutation conditions, and screening efficiency. It is necessary to adopt appropriate mutation methods for different algal strains. A combination of different mutation methods can also be used by applying higher mutation pressures in order to obtain the desired mutant strain.

Culture parameters for microalgae are typically species-specific, requiring individualized culture processes for each microalgae strain to achieve high-quality algal cultures. While most microalgae cultures adopt a one-stage culture mode. The culture conditions have no change during the whole process from microalgae growth to fucoxanthin accumulation (Heo et al., 2010; Petrushkina et al., 2017; Lu et al., 2018; Wang et al., 2018; Li et al., 2019; Marella and Tiwari, 2020; Mc et al., 2020; Kanamoto et al., 2021; Zhu et al., 2021; Jin et al., 2022), as shown in Supplementary Table 1 .

However, the one-stage mode cannot solve the contradiction between biomass and metabolite production accumulation. It cannot fulfill the demands of industrial production. Microalgae metabolites are often produced under extreme conditions that may inhibit their growth. If the conditions for metabolite accumulation are met, it can lead to the death of the algal cells, while the conditions for microalgal growth are not satisfied for pigment accumulation.

In contrast, the two-stage culture mode separates periods of microalgal growth and product accumulation. In Stage I, provided sufficient cell factories are provided, while and Stage II optimizes growth conditions (e.g, autotrophic, heterotrophic, batch sequential, nutrient conditions) to enhance metabolite production (Wan et al., 2015), as shown in (Chang et al., 2018; Chiang et al., 2020; Dambek et al., 2012; Erdogan et al., 2021; Fierli et al., 2022; Gao et al., 2020; Kim et al., 2010b; Lakey-Beitia et al, 2019; Li et al, 2000; Li et al, 2021; Masse et al, 2004; Okcu et al., 2021; Qin et al., 2013; Tachihana et al., 2020; Wei et al., 2022; Wu et al., 2011; Yang and Wei, 2020; Zhu et al., 2021) Table 1 . Compared to separate cultivation, the two-stage mode offers advantages such as high product yield, energy saving, environmental protection and a wide range of applications (Liyanaarachchi et al., 2021). Researchers have successfully improved the fucoxanthin contents and blue light amplification yield using two-stage photofermentation techniques. Yang et al. (Yang et al., 2023). raised the fucoxanthin content and yield by 45.98% and 48.3% reperceiving a two-stage culture technique. The highest recorded fucoxanthin yield among available results was obtained by Yang et al., measuring 8.22 mg/d·L (Yang et al., 2020). Li et al. achieved a fucoxanthin yield of 16.5 mg/d·L by employing a two-stage culture technique involves in high-density fermentation in the dark and blue-white light as a light source (Lu et al., 2018). The two stages of cultivation are detailed in Table 1 . In conclusion, the two-stage culture method is considered to be a viable approach.

Similar to other anti-inflammatory drugs, fucoxanthin has been found to play an anti-inflammatory role through the down-regulation of the release of relevant inflammatory mediators. It’s inhibition of the enzymatic activities, which are associated with inflammation induction in macrophages RAW264.7 (Heo et al., 2010; Kim et al., 2010a). Fucoxanthin has demonstrated beneficial effects in various conditions, such as ulcerative colitis (Yang et al., 2020), uveitis (Shiratori et al., 2005), and contact hypersensitivity (Sakai et al., 2011; Namkoong et al., 2012). In a colitis model using mice, fucoxanthin inhibited NF-κB and COX-2 expression, resulting in significant improvement of histological damage in the colon (Yang et al., 2020). Fucoxanthin has also been shown efficacy in treating uveitis in an LPS-induced inflammation rat model (Li et al., 2020). Moreover, fucoxanthin has been shown effectively alleviate dinitrofluorobenzene-induced contact hypersensitivity in BALB/c mice (Sakai et al., 2011). And prevent allergic diseases by inhibiting IgE-antigen complex-stimulated RBL-2H3 cells (Namkoong et al., 2012).

In previous studies, mechanistic studies of fucoxanthin have focused on the classical NF-κB and MAPK-related pathways. Fucoxanthin treatment has been shown to dose-dependently reduce the inflammatory factor expression levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) by inhibiting the MAPK and NF-κB pathways (Heo et al., 2010; Kim et al., 2010a). There are other related signaling pathways, such as the inflammasome, which is composed of NOD-like receptor thermal protein domain associated protein (NLRP), apoptosis-associated speck-like protein (ASC), and cysteinyl aspartate specific protein (caspase). Li et al (Li et al., 2020). found that fucoxanthin attenuated palmitate-induced transcriptional of NLRP3 inflammasomes for anti-inflammatory efficacy. Similarly, the union of fucoxanthin and rosmarinic acid has been shown to reduce the inflammatory response by downregulating inflammasome components including NLRP3, ASC, and caspase-1, as well as interleukin IL-1β production, according to Rodrguez-Luna et al., (Rodríguez-Luna et al., 2019). According to these studies, the product may have a protective impact by downregulating the inflammasome and inflammatory factors.

In this line, due to its anti-inflammatory activity, this carotenoid has been proposed as a protective compound. Given its promising anti-inflammatory effect, fucoxanthin holds potential as an independent anti-inflammatory drug or as a synergizedstic agent with other therapeutic drugs for other diseases to exert anti-inflammatory effect treatment of various diseases.

Fucoxanthin is a very powerful antioxidant. Its six-oxygen-atom propylene structure makes fucoxanthin extremely reactive to free radicals. Oxidative stress is brought on by an increase in reactive oxygen species (ROS). Heo et al., (Heo et al., 2008). induced oxidative stress in Vero cells using H₂O₂, and the addition of fucoxanthin significantly reduced intracellular ROS production while also dose-dependently inhibiting oxidative-induced cellular damage. Fucoxanthin may scavenge ROS and free radicals by means of a three-step process that involves electron transfer, dehydrogenation, and addition (Rao and Rao, 2007). Additionally, fucoxanthin has demonstrated its efficacy in modifiedying skin inflammation and skin damage caused by UV-induced photo-oxidative stress (Ichihashi et al., 2003; D’Orazio et al., 2013). When fucoxanthin isolated from algae was incorporated into sunscreen at 0.5% (w/v), it inhibited the formation of ROS significantly in reconstructed skin cells and HaCaT cells (Tavares et al., 2020). Furthermore, intracellular ROS and oxidative stress were lower in cells exposed to UV-B radiation than in cells without different concentrations of fucoxanthin (Heo and Jeon, 2009). Its powerful anti-oxidant qualities protect the skin from oxidative stress-related skin damage and aging.

Other than directly interacting with free radicals, fucoxanthin enhances the synthesis of related proteins and antioxidant enzymes. Resulting in increased plasma antioxidant enzyme activity, total antioxidant capacity, and mRNA levels of Nrf2 (Liu et al., 2011; Ha et al., 2013). It also promotes the synthesis of antioxidant proteins such as heme oxygenase-1 (HO-1) and (NAD(P)H): quinone oxidoreductase 1 (NQO-1) through activation of the Nrf2/ARE system, thereby exerting its antioxidant activity in BNL CL2 cells from murine hepatic (Liu et al., 2011). Similarly, fucoxanthin activates the Nrf2 pathway and the gene NQO1, which reduced oxidative stress under high-fat diet feeding1 (Ha et al., 2013). Moreover, fucoxanthin has been found to alleviate oxidative stress by retinol deficiency in rats by modifying the Na⁽⁺⁾-K⁽⁺⁾-ATPase, catalase (CAT) and glutathione S-transferase (GST) activities (Ravi Kumar et al., 2008).

Collectively, these findings highlight the potent antioxidant activity of fucoxanthin. Specifically, fucoxanthin, a microalgal product, is a natural green substance. It is expected to become a valuable antioxidant in the food, pharmaceutical, and cosmetics industries in the future.

Fucoxanthin can exhibit direct antitumor effects or work in conjunction with antitumor drugs to enhance their efficacy. Experimental studies have demonstrated that fucoxanthin impacts various types of cancer by promoting apoptosis (Jin et al., 2018; Yu et al., 2018). Yu et al., (Yu et al., 2018). suggested that fucoxanthin may decrease proliferation and induce apoptosis through the JAK/STAT signaling pathway, leading to cell arrest at the S phase in gastric cancer cells (SGC-7901) and at the G2/M phase in gastric cells (BGC-823). It also inhibits proliferation of cancer cells and blocking the cell cycle (Das et al., 2008) (Das et al., 2008; Hou et al., 2013; Liu et al., 2013; Long et al., 2020). Liu et al (Liu et al., 2013). found that fucoxanthin pretreatment increased the chemotherapeutic efficacy of cisplatin on human hepatoma HepG2 cells by potentially altering the DNA repair system associated with ERK, p38, and PI3K/AKT pathways, which subsequently increased cisplatin-induced apoptosis in cancer cells. Das conducted surveys showing that fucoxanthin-rich methanolic extract reduced the viability of HepG2 cells and induced G0/G1 cell cycle arrest through proteasomal degradation and inhibition of cell cycle protein D synthesis (Das et al., 2008). The effects of fucoxanthin on antitumor activity are illustrated in Figure 4 .

Therefore, it has a therapeutic effect on cancers. Fucoxanthin has shown potential in treating nasopharyngeal cancer (Long et al., 2020), cervical cancer, cervical cancer (Hou et al., 2013; Jin et al., 2018), lung cancer (Moreau et al., 2006), breast cancer (Wang et al., 2019) and other cancers to promote apoptosis and inhibit of tumor cells proliferation. In addition to its direct pharmacological effects, the anti-inflammatory and antioxidant properties of fucoxanthin contribute to its anti-tumor activity. Shin et al., (Shin et al., 2020). revealed that fucoxanthin may improve the efficacy of targeted anticancer drug therapy by reduce oxidative stress on tumor cells, while increasing oxidative stress on tumor cells.

Therefore, fucoxanthin can be used in anti-cancer treatment and in combination with anti-cancer drugs to assist anti-cancer treatment. At the same time, it can be used in combination with some anti-cancer drugs to improve the targeting of tumor cells and prevent damage to healthy cells.

Alzheimer disease (AD) is a devastating neurodegenerative disorder (Shih et al., 2021). Fucoxanthin has shown potential neuroprotective effects against these diseases.

There is often associated with the binding of amyloidogenic fibers (e.g., Aβ, tau proteins) in Alzheimer’s disease. Drug design analysis and molecular docking simulations conducted by Lakey-Beitia et al., (Shih et al., 2021). revealed the action of carotenoids on Aβ amyloidogenic fibers. They found that carotenoids can bind to Aβ through hydrogen bonding and van der Waals interactions. These findings are consistent with the findings ofstudies by Xiang et al., (Xiang et al., 2017). and Yang et al., (Yang et al., 2021),which also showed that fucoxanthin inhibits Aβ assembly.

Additionally, Aβ deposition furthermore results in many issues that induce oxidative stress and neuronal cell death. In the mouse hippocampal regions, fucoxanthin has been shown to reduce oxidative stress in neuronal cells, increase brain-derived neurotrophic factor expression, and expand ChAT-positive areas (Xiang et al., 2017). This helps to maintain neuronal cell viability (Xiang et al., 2017). Fucoxanthin also prevented neuronal apoptosis and intracellular reactive oxygen stress by Aβ oligomer through activating the PI3K/Akt cascade and inhibiting the ERK pathway in SH-SY5Y cells (Lin et al., 2017). Zhu et al., (Zhu et al., 2021). in vitro research showed that 5-10 μM fucoxanthin reduced the activity of the senescence marker SA-β-galactosidase. Another in vitro study demonstrated that fucoxanthin modulated antioxidant enzymes such as superoxide dismutase (SOD) to exert antioxidant effects on neuronal cells, inhibited Aβ_1-42 induced apoptosis (Zhu et al., 2021).

The available evidence supports the neuroprotective effects of fucoxanthin and highlights the potential marine-derived carotenoids as novel strategies for preventing or treating dementia. Figure 6 illustrates the mechanism of its anti-Alzheimer activity.

Fucoxanthin can be a natural antimicrobial agent. Although it has antibacterial activity against both Gram-positive and negative bacteria, it does not show activity against strict anaerobic bacteria (Karpiński and Adamczak, 2019). Liu Z et al., (Liu et al., 2019). reported the antimicrobial properties of fucoxanthin against human pathogens (Streptococcus agalactiae, Staphylococcus epidermidis, and Staphylococcus aureus), indicating that fucoxanthin effectively inhibits their growth. Peraman M et al (Peraman and Nachimuthu, 2019). screened methanolic extracts of marine microalgae fucoxanthin for antimicrobial activity. Among them, both the extract of Dunaliella salina and Thalassiosira extract showed better antibacterial activity against bacteria and fungi (minimum inhibitory concentration MIC: 40 mg/mL), whereas the bacterial species acted were different. Transmission electron microscopy was applied for determining the morphological changes in bacterial after fucoxanthin treatment (El Shafay et al., 2016). Perforation of cell wall, leakage of cytoplasmic contents, severe distortion of outer cell shape, inner chromatin mild scattered cytoplasmic vacuolation, rupture of cell wall, and decreased cell size for bacteria treated with fucoxanthin-containing seaweed extracts (El Shafay et al., 2016). And carotenoids induce the accumulation of a lysozyme that can digest bacterial cell walls. The antimicrobial mechanism of fucoxanthin may be associated with it (Abu-Ghannam and Rajauria, 2013).

Based on these findings, fucoxanthin is expected to contribute to addressing the issue of bacterial drug resistance.

In terms of antiviral activity, fucoxanthin has been found to inhibit the activation of Epstein-Barr Virus at lower concentrations (Tsushima et al., 1995). Additionally, there is a hypothesis that the consumption of fucoxanthin-containing dietary seaweeds may provide resistance against COVID-19 damage through various mechanisms, but further investigation is needed to understand its pharmacological activity and mechanism (Tamama, 2021).

During the process of angiogenesis, the vascular endothelium releases proteases and migrates through the extracellular matrix in order to proliferate and differentiate into new blood vessels. Ponesakki G et al (Ganesan et al., 2013). conducted a study using human umbilical vein endothelial cells (HUVEC) to clarify the molecular mechanisms of fucoxanthin, an antivascular compound. Their findings revealed that fucoxanthin inhibits FGF-2-mediated intracellular signaling proteins, thereby suppressing the migration of endothelial cells. Their differentiation into tubular structures was also inhibited. In in vitro angiogenesis assays, fucoxanthin in doses more than 10 μM demonstrated significant suppression of HUVEC tube formation and proliferation (Sugawara et al., 2006). Moreover, in an ex vivo angiogenesis assay, fucoxanthin exhibited a dose-dependent suppression of microvessel outgrowth (Sugawara et al., 2006).

Angiogenesis is crucial for both the healing of wounds and the advancement of illnesses like rheumatoid arthritis and cancer. Many pathological conditions, such as tumors, atherosclerosis, and SARS-CoV-2, are known to be associated with angiogenesis (Viallard and Larrivée, 2017). Studies indicate that fucoxanthin is a potentially useful product that can be used to treat angiogenesis-related illnesses in a secure and efficient manner.

Osteoclasts and osteoblasts work in tandem to regulate the process of bone development and formation. Treatment with 2.5 μM fucoxanthin inhibited osteoclast RAW264.7 differentiation and induced osteoclast apoptosis to inhibit osteoclast formation. Notably, fucoxanthin induced apoptosis effect on osteoclasts was stronger compared to osteoblasts (Das et al., 2010). You-Jung et al (Ha et al., 2021). investigated the effects of fucoxanthin on osteoblast differentiation and its regulatory pathways. Their results demonstrated that fucoxanthin altered the expression of mitogen-activated protein kinase and Nrf2, leading to a significant inhibition of osteoclast differentiation and bone resorption.

Therefore, fucoxanthin potentially holds promise as a therapeutic agent for skeletal diseases, for example, rheumatoid arthritis and osteoporosis.