Lycopene was an isoprenoid unsaturated olefin compound and a fat-soluble carotenoid. Lycopene consists of 40 carbon chains, including 11 conjugated double bonds and 2 non-conjugated double bonds (Figure 2). Its molecular formula is C₄₀H₅₆, its relative molecular mass is 536.85, and its melting point ranges from 172 to 175°C. Lycopene has obvious lipophilicity and is easily soluble in organic solvents, such as Hexane (C₆H₁₄), chloroform (CHCl₃), carbon disulfide (CS₂), petroleum ether, acetone (C₃H₆O) and benzene (C₆H₆), and so on. However, Lycopene is insoluble in water, and methanol, ethanol, and is sensitive to light, acid, catalysts, high temperatures, and metal ions (22). In nature, lycopene has a high degree of unsaturation and mainly appears in the form of the all-trans isomer, which easily oxidatively degrades and undergoes an isomerization reaction under the influence of light, temperature, or chemical reactions, converting from all-trans isomers to mono-cis or poly-cis isomers (23). The most stable form of lycopene among all isomers is said to be 5-cis, which is followed by all-trans, 9-cis, 13-cis, 15-cis, 7-cis, and 11-cis (24). Consequently, all-trans isomers comprise 90% of the lycopene found in tomatoes, whereas most of the processed tomato products exist in the form of the cis isomer.

Lycopene is harmless to animals and humans and has certain benefits, which whether in the form of preparation or crystallization, was not genotoxic under stable conditions (25), Lycopene were not toxic to rabbit lymphocytes and did not produce any mutagenic activity (26). Similar results have been obtained in subchronic and chronic safety studies in mice (27). Additionally, it was concluded by Rao et al. (7) that healthy individuals who consume 5 to 75 mg of lycopene daily will not experience any negative effects. At the same time, Kong et al. (28) indicated that a daily intake of 3 g/kg of lycopene from food will not harm the human body. Therefore, lycopene is considered a safe Non-toxic substance.

Under normal physiological conditions, the generation and elimination of free radicals were always in a state of dynamic balance. When oxidative stress occurs, this dynamic balance will be broken, and fat, protein, and DNA in the body will be damaged, leading to a variety of diseases (29). The advancement of animal husbandry is gravely threatened by oxidative stress, which brings huge economic losses to the industry (30). Antibiotics were once useful antioxidant medications that might enhance animal immunity, growth performance, and disease prevention. However, animal production, human health, and environmental sustainability are threatened by antibiotic resistance and residues (31). Since the European Union (EU) banned the use of antibiotics in animal feed in 2006, and researchers have been trying to find plant-based feed supplements as safe antibiotic alternatives (32). In July 2020, China announced that livestock farming had officially entered a new era of banning the use of antibiotics in feed (33). Therefore, developing natural, healthy, and safe antibiotic alternatives for animal husbandry is one of the hot spots in modern feed research.

Relevant reports indicated that lycopene due to its polyunsaturated structure, not only directly scavenged free radicals, but also indirectly scavenged free radicals by regulating the enzymatic antioxidant defense system and enzymatic oxidative damage system (34). Therefore, lycopene protects proteins, DNA, and lipids in the body from oxidative damage, thereby reducing oxidative stress in the body and maintaining animal health.

The lipid-lowering mechanism of lycopene was shown in Figure 4. Lycopene could inhibit lipid synthesis in the body through multiple pathways of action, and at the same time accelerate the rate of lipid transport and mobilization efficiency, thereby achieving lipid-lowering effects. Peroxisome proliferator-activated receptor α ( PPARα ), as the most important factor in the lipid-lowering mechanism of lycopene, plays a decisive role in the lipid-lowering function of lycopene. Relevant research has shown that PPARα could activate β-oxidation-related genes, thereby increasing the expression of mRNA of related genes, and promote the uptake of lipid mitochondria in body cells, accelerate lipolysis, and then play an important role in lipid metabolism in the body. PPARα not only orchestrates the coordination of lipoprotein metabolism but also directly or indirectly controls the lipogenesis pathway in the liver (71, 72). In another study, lycopene was found to possess another important mechanism of lipid metabolism. Lycopene increased the gene expression of PPARγ coactivator 1α ( PGC1α ), PPARα , retinoic X receptor α ( RXRα ) and retinoic acid receptor α ( RARα ) in the liver of breeding hens, which downregulated the expression of liver fatty acid binding protein 1 ( FABP1 ), liver fatty acid binding protein 10 ( FABP10 ) and jejunum fatty acid transporter 4 ( FATP4 ) genes. Moreover, lycopene also upregulated the expression of PPARγ , RXRγ , RXRα , and duodenal RXRα genes in the jejunum. Therefore, lycopene accelerates the fat metabolism rate in the body and reduces fat deposition through this pathway (55). Lycopene could activate the AMP-activated protein kinase/ Sirtuin 1/peroxisome proliferator-activated receptor-γ-coactivator 1α (AMPK/SIRT1/PGC1α) or inhibit signal transducer and activator of transcription 3 (STAT3) biosynthetic signaling pathway. and then lycopene upregulated the mRNA expression levels of SIRT1 and inhibited the mRNA expression levels of sterol regulatory element binding proteins (SREBPs), fatty acid synthase ( FAS ), and acetyl-CoA carboxylase 1 ( ACC1 ) genes, thereby inhibiting the synthesis of lipids, and ultimately reducing the levels of total cholesterol (T-CHO), triglycerides (TG), and low-density lipoprotein (LDL-C) in the serum of mouse livers and broiler chickens (13, 14, 56). Moreover, lycopene reduced lipid synthesis and prevented mitochondrial dysfunction induced by palmitate, thereby reducing the risk of nonalcoholic fatty liver disease (NAFLD) in mice (13, 14, 56, 57). In addition, it was concluded by Huang et al. (73) and Albrahim et al. (48) that lycopene could improve liver damage caused by a high-fat diet in mice. Moreover, Lu et al. (74) also reported that lycopene reduced TG in HepG2 cells caused by oleic acid and palmitoleic acid. Alvi et al. (53) demonstrated that lycopene inhibits the activity of HMG-CoA reductase (HMGR) and proprotein convertase subtilisin / kexin type 9 (PCSK-9) transcription. Therefore, lycopene reduced the synthesis of T-CHO and the endocytosis of LDL-C by inhibiting the activity of HMGR and LDL-C receptors, thus achieving the purpose of lipid-lowering (54). Moreover, lycopene enhanced the activity of AMP-activated protein kinase ( AMPK-P ) and downregulating ATP citrate-raising lyase ( ACLY ). Ultimately, the levels of MDA, HMG-CoA reductase , FAS , ACLY , and TNF-α were reduced and the levels of AMPK-P and GSH were increased in diabetic hyperlipidemia rats (75).

In conclusion, through a review of many existing studies, it was found that there are four main pathways for the lipid-lowering mechanism of lycopene. Lycopene activates the PPARα and AMPK/SIRT1/PGC1α pathways, thereby downregulating the expressions of FABP1 , FABP10 , ACC1 and FAS . In addition, lycopene could also downregulate the expression of ACC1 and FAS and LDL-C endocytosis by inhibiting the STAT3 biosynthetic signaling pathway and the HMGR/PCSK-9 transcriptional activity pathway, ultimately achieving a lipid-lowering effect.

The anti-cancer mechanism of lycopene was shown in Figure 5. There were in vitro and in vivo research has shown that lycopene has an important anticancer effect, which inhibited the proliferation of cancer cells through antioxidant activity, regulation of anti-inflammation, growth factor signaling, apoptosis induction, and cell arrest, such as anterior prostate cancer, cervical cancer, breast cancer, melanoma, ovarian cancer, oral cancer, hepatocellular carcinoma, lung cancer, and other cancer cells (13, 14, 80–88). The content of Serum lycopene and lycopene intake was inversely proportional to the probability of cancer (10). Inducing cancer cell apoptosis is one of the most important anti-cancer mechanisms of lycopene. The main pathway of apoptotic decomposition of cells is the activation of BH3-only protein (BH3) by DNA damage, which directly activated B⁃cell lymphoma, leukaemia⁃2⁃associated X protein (BAX), and B⁃cell lymphoma, leukaemia⁃2⁃associated K protein (BAK) and made them become homologous oligosaccharides. At this time, due to the penetration of outer mitochondrial members, mitochondrial intermembrane proteins are released in the cytoplasm and combine with Apaf-1 to form procaspase-9-activating a heptameric protein complex called the apoptosome, which ultimately activates caspase-3 and caspase-7 cleaves the target protein, led to apoptotic breakdown (77). Moreover, in “type II” cells, such as hepatocytes, the mitochondrial amplifying loop activates the effector caspase and then releases SMAC to downregulate XIAP expression to mitigate its mediated caspase inhibition (77). Previous studies have shown that lycopene reduced carcinogenesis by inhibiting the phosphatidyl-inositol 3-kinase/serine–threonine kinase (PI3K-AKT) signaling pathway, similarly, lycopene induced apoptosis by downregulating B, cell CLL/lymphoma-2 (BCL-2), and upregulating BAX (79, 89). Previous records have shown that lycopene might increase the levels of Bax and E-cadherin and downregulate the levels of N-cadherin, phosphatidylinositol 3-kinase (p-PI3K), protein Kinase B (p-AKT), BCL-2, and phosphatidylinositol 3-kinases (PI3K)/AKT/mammalian target of rapamycin (p-m-TOR). The inactivation of PI3K/AKT/m-TOR signaling inhibits epithelial-to-mesenchymal transition apoptosis in oral cancer cells (13, 14). Moreover, lycopene could inhibit the proliferation of human breast cancer MCF-7 cells and promote their apoptosis by upregulating the gene expression of p53 protein (p53) and Bax (78).

It was concluded by Ozkan et al. (10) that that lycopene could play an anti-inflammatory and antioxidant role in ovarian cells by upregulating Nrf2 or downregulating nuclear factor-kB ( NF-kB ) and STAT3 signals, thus inhibiting the occurrence of spontaneous ovarian cancer in laying hens. Furthermore, lycopene also downregulated the mRNA expression of integrin β1 ( ITGB1 ), integrin α5 ( ITGA5 ), focal adhesion kinase ( FAK ), integrin-linked kinase ( ILK ), matrix metalloproteinase 9 ( MMP9 ) and the expression of epithelial to mesenchymal transition (EMT) inhibits the activity of mitogen-activated protein kinase ( MAPK ) and reduced the mRNA expression level of the ovarian cancer biomarker CA125, thereby inhibited the proliferation of primary ovarian cancer cells and metastatic cells in mice (76). Cheng et al. (90) concluded that low-dose lycopene increased the expression level of 8-oxoguanine DNA glycosylase ( OGG1 ), Nei-like DNA glycosylase ( NEIL1 , NEIL2 , NEIL3 ), and connexin 43 (Cx43). Similarly, it also upregulated the expression level of scavenger receptor (SRB) protein SR-B1, thereby inhibiting lung cancer by improving gene stability and inhibiting smoke-induced oxidative stress. Lycopene inhibited the proliferation of ferret liver cancer and lung cancer cells induced by tobacco carcinogens by inhibiting the protein expression levels of lung α7 nicotinic acetylcholine receptor or NF-kB and cytochrome P450E1 (80). Additionally, it was concluded by Jhou et al. (91) that 2.5 μM lycopene could significantly downregulate the activities of NADPH oxidase 4 ( NOX4 ), matrix metalloproteinase 2 ( MMP-2 ) and matrix metalloproteinase 9 ( MMP-9 ), and then inhibited the migration of human hepatic adenocarcinoma SK-Hep-1 cells. Moreover, inhibiting the migration of human umbilical vein endothelial cells and the activity of vascular endothelial growth factor are also two ways in which lycopene could effectively prevent cancer (92, 93).

In conclusion, Lycopene could induce mitochondrial apoptosis induced by the inactivation of the growth factor ( FASR , VEGFR , IGF-1R , and PDGFR ), mainly inducing BH3 dependent and independent activation of BAX and BAK, Ras/RAF/MAPK, and PI3K/AKT/PKB signaling pathways to achieve anticancer effects. When these pathway pathways are activated. Many related anti-cancer factors will be activated, thereby regulating the cell cycle, inflammation, apoptosis, metastasis, angiogenesis, and so on, ultimately achieving the purpose of anti-cancer.

The anti-inflammatory mechanism of lycopene was shown in Figure 6. Lycopene improved inflammation in the body by upregulating and downregulating many signaling channels and limited the transcription and expression of inflammatory mediator-related factors (34). As a key transcription factor involved in body inflammation and cellular immunity, NF-kB will participate in the transcription and synthesis of inflammatory cytokines and chemokines in acute inflammatory responses after activation and has powerful anti-apoptotic and endothelial anti-inflammatory effects. Therefore, it plays an important role in the body’s anti-inflammatory and immune regulation (99, 100). A previous study by Ugbaja et al. (101) indicated that lycopene reduced oxidative stress and downregulated the toll-like receptor-4 (TLR4) / NF- ĸ B-p65 axis in female Wistar rats, thereby mitigating the neuroinflammation caused by palmitic acid (PA). Furthermore, the reduction of lipopolysaccharide (LPS) induced neuroinflammation in male C57BL/6 J mice is affected by lycopene through the regulation of MAPK , NF-κB , and Nrf2 signaling pathways (95). It was concluded by Zhao et al. (102) that lycopene mediated the Nrf2/NF- ĸ B pathway in CD-1 mice, which reduced neuroinflammation brought on by oxidative stress. Lycopene could activate the Nrf2/HO-1 signaling pathway, thereby inhibited the activation of the NF - κB and STAT3 pathways caused by interleukin-1β (IL-1β), limited tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase ( iNOS ) gene transcription, and then reduced TNF-α, IL-6 and prostaglandin content, and slow down arthritis in mice (98). Moreover, lycopene also reduced arthritis by activating the Kelch-like epichlorohydrin-related protein-1 ( Keap1 )-Nrf2 signaling pathway (97). In improving cellular inflammation, lycopene has been reported to stimulate PPARγ gene transcription by inhibiting MAPK and NF - κB signaling, on the other hand, lycopene also activated the Nrf2/HO-1 pathway, enhanced autophagy in liver macrophages, inhibited the expression of nucleotide-binding oligomerization domain-like receptor protein 3 ( NLRP3 ), and reduced the secretion of IL-1β, IL-6, interleukin-8 (IL-8), and TNF-α ultimately achieves the purpose of improving macrophage inflammation (94, 96). Previous research has shown that the combination of quercetin and lycopene reduced the expression levels of modulatory metalloproteinase 7 ( MMP7 ), MDA, MPO, and hydroxyproline, while the expression levels of SOD and GSH was elevated and has the potential to resolve inflammation induced by ochratoxin A ( OTA ) in rats (103). Notably, lycopene inhibited monocyte adhesion and migration induced by high mobility group protein box 1 (HMGB1) produced by necrotic cells and immune cells exposed to pro-inflammatory signals by decreasing the gene expression of cell adhesion molecules. Consequently, it reduced LPS-induced HMGB1 release and HMGB1-mediated secretion of TNF-α and secretory phospholipase A2, and the body finally exerts its anti-inflammatory function (104, 105).

In addition to inhibiting inflammation in the body, lycopene also has the function of enhancing cellular immunity and humoral immunity. The immunomodulatory of lycopene was shown in Figure 7. Furthermore, lycopene also has the function of protecting lymphocytes, promoting the transformation of T lymphocytes, increasing the CD4+/CD8+ ratio, and enhancing the activity of natural killer cells (109–111). It was concluded by Sarker et al. (112, 113) that lycopene reduced the damage aflatoxin B1 (AFB₁) caused to broiler intestinal immune function by upregulating the production of claudin-1 (CLDN-1) mRNA and lowered the levels of the inflammatory cytokine interferon-γ (IFN-γ) and IL-1β. Similarly, Hidayat et al. (19) also obtained the same result. Lycopene might work by encouraging T-cell transition, raising the CD4+/CD8+ ratio, and concurrently lowering inflammatory cytokine levels, all of which would enhance rats’ immunity (106). Moreover, lycopene could also ensure the health of the sow placenta by reducing the expression level of placental inflammatory factors and improving immunoglobulin content, antioxidant capacity, placental lipid transport, and lipid metabolism (16). Other studies have found that lycopene could regulate the efficiency of IFN-γ and IL-2 production by mouse T lymphocytes or indirectly activate T cells (108). Furthermore, lycopene could increase the production of spleen B lymphocytes and serum immunoglobulin G content in mice, thereby improving the immune function of mice (107).

In conclusion, lycopene has potent anti-inflammatory and immunoregulatory properties. It could promote the development of B and T lymphocytes, stimulate the normal differentiation of T cells, along regulate the production and release of factors linked to inflammation.

Lycopene was widely used in poultry production because of its strong antioxidant, anti-inflammatory, and immune-regulating effects. In the current poultry research reports, lycopene was mainly used in poultry feed as a feed additive. It could be concluded from Table 2 that lycopene could reduce the feed conversion ratio (FCR), belly fat weight, and the levels of MDA, LDL-, TG, T-CHO, IFN-γ, IL-1β, ROS, and H₂O₂ in poultry. In addition, lycopene reduced the rate of drip loss, cooking loss, and pH drop in broilers. The incorporation of lycopene in poultry diets could improve the growth performance, feed intake, and meat quality of poultry. Moreover, lycopene could also improve the GSH-PX, GSH, GST, SOD, immune organ index, and HDL-C indicators of poultry. In gene expression, lycopene increased the mRNA expression levels of Nrf2, ABCG5, ABCG8, Cludin-1, PGC1α, PPARα, RXRα, RARα, and RXRγ. Furthermore, lycopene reduced the activity of acetyl-CoA carboxylase, sterol regulatory element binding protein 1 (SREBF1), fatty acid synthase, microsomal triglyceride transfer protein (MTP), Niemann-Pick C1Like1 ( NPC1L1 ), cholesterol O-acyltransferase (ACAT) 2 ( ACAT2 ), Which lycopene also reduced the mRNA expression levels of SREBP1c, LXRα, ACLY, FABP1, FABP10 and FATP4. Lycopene increased the activity of intestinal digestive enzymes amylase, lipase, glutamine-cysteine ligase, mitochondrial glutathione, electron transport chain complex III, V, and manganese superoxide dismutase (MnSOD) in poultry. A previous study by Ayo et al. (116) indicated that lycopene could increase the concentration of plasma triiodothyronine concentration and the count of preovulatory follicles and white follicles. Furthermore, the temperature of the cloacal is reduced, thus increasing the reproductive rate of laying hens.

Lycopene has been widely used in animal production because of its special beneficial functions to animals. There are surprisingly few reported lycopene-related outcomes in ruminant production, according to the most recent published reports. It could be concluded from Table 3 that supplementing lycopene to sheep and goat diets could improve T-AOC, CAT, GSH-Px, SOD, vitamin E, production performance, slaughter performance, and meat quality. Additionally, it was concluded by Fallah et al. (15) that lycopene could enhance immunological markers, sex hormones, and milk quality, which promote the breast development of ewes. The incorporation of lycopene in diets reduced the levels of T-CHO, TG, LDL-C, and MDA, which reduced FCR, Muscle L* value, the content of muscle fat, lipid oxidation, and protein oxidation (including thiobarbituric acid-reactive substance and carbony l) in sheep and goats. In addition, in an experiment on the effect of lycopene on ram semen, it was concluded that supplementing lycopene improved the individual motility of goat sperm and reduced sperm mortality and abnormal sperm content. The application of lycopene in cattle diets production is rarely reported. Lycopene improved the milk quality, embryo development, and quantity of cattle, and reduced ROS levels and the expression of genes such as NF-kB, iNOS, BCL-2 and COX2.

In conclusion, we have reviewed many existing literature reports and found that the incorporation of lycopene in diets of poultry and ruminant feeding could improve growth performance, meat quality, and reproductive performance, but the optimal amount of lycopene has a large span. Existing reports have found that the optimal amount of lycopene added to poultry feed ranges from 30.00 mg/kg to 400.00 mg/kg. Additionally, in the feeding of ruminants, the amount of lycopene added to the feed should not exceed 200.00 mg/kg. From the data obtained, it can be concluded that the study of the optimal addition amount of lycopene in poultry and ruminant feed is still a hot topic, which needs to be further verified in the future.