The pro-inflammatory role of COX2 and PGE2 in the liver are illustrated by studies using diet to induce chronic inflammation or bacterial toxins/physical injury to induce acute inflammation (Figure 4). During chronic liver injury conditions, such as NAFLD and NASH, COX2 metabolism is implicated where both COX1 and COX2 expressions are induced (Lampiasi et al., 2006; Henkel et al., 2018; Garcia-Jaramillo et al., 2019; Sztolsztener et al., 2020). EPA feeding inhibits NAFLD (Ishii et al., 2009; He et al., 2010; Albracht-Schulte et al., 2019; Chen et al., 2021a) suggesting that AA-derived eicosanoids play a role in the development of NAFLD. Consistently, interventions that reduce NAFLD is associated with decreased PGE2 in circulation (Cansancao et al., 2020; Maciejewska-Markiewicz et al., 2022). Furthermore, pharmacological inhibition of COX2 with celecoxib attenuates hepatic steatosis and associated inflammation (Chen et al., 2011; Wu et al., 2016; Liu et al., 2018; Zhang et al., 2022). AKT kinase, NFκβ and autophagy are implicated in this role of COX2. In addition, deficiency of PGES2 also led to reduced liver injury and inflammation in Methionine-choline deficient (MCD) diet induced NASH (Zhong et al., 2022), suggesting that PGE2 maybe driving the effects of COX2. In response to acute injury, liver also upregulates the expression of COX2 and production of PGEs and TXs (Bowers et al., 1985; Reilly et al., 2001; Bezugla et al., 2006; Miller et al., 2007; Shimada et al., 2020). COX2 inhibition resulted in reduced neutrophil infiltration and protection against ischemia reperfusion (I/R) injury (Kuzumoto et al., 2005; Ozturk et al., 2006; Tolba et al., 2014). In LPS/Galactosamine (GalN) induced acute liver injury model, decreasing PGE2 with hepatocyte-targeted expression of 15-PGDH led to less hepatic apoptosis/necrosis (Yao et al., 2017). Thus, COX2 and its metabolites indeed play a proinflammatory role during both acute and chronic liver injury (Figure 4).

While COX2 and PGE2 induce inflammation, suggesting that they might promote further liver injury, genetic studies have also demonstrated a hepatoprotective effects for these lipids. This cytoprotective effects is responsible for hepatocyte regeneration after injury (Figure 4). Using the apolipoprotein E (ApoE) promoter to drive the expression of COX-2 led to protection against diet-induced liver steatosis (Frances et al., 2015). Consistent with this result, global loss of PGES1 augmented hepatocyte apoptosis and increased liver inflammation, particularly TNFα releases when treated with LPS (Henkel et al., 2018). As COX enzymes and PGE2 are also expressed in liver hepatocytes, these genetic studies together suggest cell- and context-specific functions of COX2-PGE2 axis in liver injury. Supporting this notion, deletion of COX2, treatment with celecoxib or CAY10526, a PGES inhibitor result in more severe toxicity/lethality induced by overdose of acetaminophen (Reilly et al., 2001; Cavar et al., 2010). Thus, the mitogenic role of PGE2 on inducing hepatocyte proliferation may have contributed to this “cytoprotection” effect of PGE2 and COX2 (Bowers et al., 1985; Tsujii et al., 1993) despite of their proinflammatory function. However, some recent data also suggests an anti-inflammatory properties of PGE2 in the cardiovascular system (Gitlin and Loftin, 2009; Kirkby et al., 2014) that might be receptor isoform mediated (Takayama et al., 2002; Tang et al., 2012). In the liver, this is supported by the accelerated development of NASH in MCD diet fed mice lacking PGI2 receptor (Kumei et al., 2018) and reduced neutrophil infiltration and protection against I/R injury in EP4 agonist treated mice (Kuzumoto et al., 2005). Therefore, a balanced pro- and anti-inflammatory function of COX2/PGE2 and their role towards cell growth and apoptosis during liver disease progression likely determine their roles at given stages of the disease (Figure 4).

Overexpression of COX-2 and PGE2 receptors is observed in most tumor types, including HCC (Koga et al., 1999; Kondo et al., 1999; Shiota et al., 1999; Sung et al., 2004; Breinig et al., 2008; Zang et al., 2017) and is further induced when coupled with HFD (Koga et al., 1999; Hamzawy et al., 2015). Expressions of COX2 also correlates with the differentiation status of liver cancer (Koga et al., 1999; Kondo et al., 1999; Shiota et al., 1999; Sung et al., 2004) where high COX-2 expression is associated with lymph vascular invasion and distant metastasis with poor 5-year survival (Tai et al., 2019). Supporting a pro-tumor role of COX-2 in HCC development, knockdown of COX-2 resulted in reduced cell proliferation and significantly decreased colony formation in cultured HCC cell lines (Austin Pickens et al., 2019). Expression of COX2 in cultured hepatocytes also suppressed caspase activity concurrent with reduced p53 and Bax expression, suggesting a role of COX-2 in apoptosis as well (Fernandez-Martinez et al., 2006). Consistently, ectopic expression of COX-2 in the livers of transgenic mice was sufficient to induce spontaneous HCC development (Chen et al., 2017), though other studies show preneoplastic lesions with minor contribution to the malignant transformation to HCC (Llorente Izquierdo et al., 2011). Further, inhibition of COX-2 attenuates HCC growth in animal models (Hamzawy et al., 2015; Ali et al., 2022) and celecoxib dose-dependently reduce tumor weight (Cui et al., 2005; Li et al., 2016). These genetic and pharmacological studies indicate a pro-tumor role of COX-2 and its metabolite in liver cancer progression (Figure 4).

As the major product of the COX2-mediated metabolites of AA(26), elevated serum PGE2 levels are associated with larger HCC tumor sizes and poor overall survival (Gong et al., 2017; Li et al., 2018; Tai et al., 2019; Pelizzaro et al., 2021). Transgenic expression of HBV X protein (HBx) that promotes tumor development also leads to increased PGE2 in the serum (Lan et al., 2022). In HCC cells, PGE2 level is associated with enhanced cell proliferation and invasion due to upregulated expression of survivin (Bai et al., 2010), c-Myc (Xia et al., 2014), and β1-integrin (Bai et al., 2014). The mitogenic effects of PGE2 has been found to be mediated via EP3 receptor in cultured rat hepatocytes in which PGE2 dose- and time-dependently induced DNA synthesis (Hashimoto et al., 1997). A role of PGE2 on inducing tumor cell invasion and migration has also been reported (Mayoral et al., 2005; Bai et al., 2009; Zhang et al., 2014a; Zhang et al., 2014b; Cheng et al., 2014; Xia et al., 2014). Consistent with a promo-tumor growth role of PGE2, genetic studies showed that overexpression of 15-PGDH suppresses while its knockdown induces the growth of HCC cells and tumor grafts (Lu et al., 2014). An opposite effect is observed when PGES1 is targeted (Lu et al., 2012).

The involvement of serine/threonine kinase AKT and mTOR in COX-2 regulated pro-tumor effects have been reported (Leng et al., 2003; Liu et al., 2005; Qiu et al., 2019; Tai et al., 2019). In steatotic livers, celecoxib blocks insulin regulated lipid accumulation via its actions on AKT (Lu et al., 2016), which has been shown to drive de novo lipogenesis (He et al., 2010; Li et al., 2013; Palian et al., 2014; Chen et al., 2021a). COX-2 also regulates apoptosis and cell proliferation in HCC via AKT signaling as dephosphorylation of AKT is observed concurrent with induction of cell death and reduced PCNA staining (Leng et al., 2003; Liu et al., 2005). The regulation of tumor suppressor PTEN, a negative regulator for AKT-mTOR signal (Tu et al., 2020), and its effect on tumor progenitor cells may play a role in the effect of COX-2 on hepatic tumorigenesis (Rountree et al., 2009; Galicia et al., 2010; Chu et al., 2014; Guo et al., 2015; Debebe et al., 2017; Chen et al., 2021b). Other signals involved in PGE2 regulated cell growth and survival includes growth factor signals (Koide et al., 2004; Fernandez-Martinez et al., 2006; Odegard et al., 2012; Tveteraas et al., 2012; Zhang et al., 2014a), mitochondrial function (Kern et al., 2006), ER stress signal (Lee et al., 2020; Su et al., 2020) as well as the HIF-1α pathway (Dong et al., 2018). A synergistic effect has been observed for sorafenib, the multikinase inhibitor used as first-line therapy for HCC and celecoxib (Cervello et al., 2013).

Thromboxanes regulate liver micro vasoconstriction functions and stimulates the release of proinflammatory cytokines that impacts platelets and recruitment of leukocytes (Iwata, 1994; Yokoyama et al., 2005). In response to LPS stimulation, TXA2 and its stable metabolite TXB2 are released from macrophages prior to PGE2, likely due to the expression of TXA2 synthase that is already present in the naïve livers (Bowers et al., 1985; Bezugla et al., 2006; Miller et al., 2007). Elevated plasma thromboxane is found to correlate with the severity of liver injury (Nanji et al., 1993; Shimada et al., 1994; Suehiro et al., 1996; Nanji et al., 1997). Treatment with TX receptor antagonist or TXA synthase inhibitor prevents the necroinflammatory changes, reduced injury and also reduces alcohol feeding induced fibrosis (Suehiro et al., 1996; Nanji et al., 1997; Ito et al., 2003; Nanji et al., 2013). In addition, reducing levels of TXA2/B2s is implicated in statin and riboflavin mediated suppressive effects on NASH induced injuries (Ajamieh et al., 2012; Wang et al., 2018). Despite this pro-inflammation/injury role, TX signal is also necessary for promoting liver regeneration. Deletion of TXA2 receptor TP or treatment with TXA2 inhibitor results in impaired ability for mice to recover from partial hepatectomy (PHx) or carbon tetrachloride (CCL4) induced injury with elevated necrosis and delayed hepatocyte proliferation (Minamino et al., 2012; Mohamed et al., 2020). Thus, similar to that of PGE2, the mitogenic function of TXA2 versus its effects towards inflammatory response determines whether TXA2 has a hepatoprotective or pro-injury/inflammation effects in any given experimental condition (Figure 4). Non-etheless, these observations indeed implicate a pro-tumorigenic role of TXA2 in modulating the tumor immune environment as well as tumor growth, though experimental data are still needed to specifically address this function of TXA2 in liver cancer. Of note, in a model of colon cancer metastasis to the liver, inhibiting TXA2 synthase showed more significant inhibition than aspirin (Yokoyama et al., 1995), suggesting that the TXA2 indeed supports a pro-tumor microenvironment.

In HCC patients, elevated leukotriene metabolites is reported (Zhou et al., 2011). Experimental evidence demonstrates that 5-LOX expression is increased in several rodent models of liver disease, including liver fibrosis induced by CCl₄ and MCD diet (Pu et al., 2021), acetaminophen-induced liver injury (Pu et al., 2016), diethyl nitrosamine (DEN)-induced HCC (Xu et al., 2011), HFD-induced NAFLD/NASH (Ma et al., 2017), and hepatic steatosis due to ApoE deficiency (Martinez-Clemente et al., 2010). Accordingly, inhibition or loss of 5-LOX attenuates or protects the mice against these conditions (Martinez-Clemente et al., 2010; Hohmann et al., 2013; Pu et al., 2016; Ma et al., 2017; Pu et al., 2021). Mechanistically, 5-LOX and its metabolite LTB4 is found to activate NF-Kβ in HCC cells (Zhao et al., 2012). Inhibition of 5-LOX and LTB4 resulted in decreased PCNA and cyclin D expression after HPx (Lorenzetti et al., 2019). A positive feedback loop for 5-LOX and FASn is identified that involves LTB4 (Chiu et al., 2019). Production of another metabolite of LOX, 5-HETE is also perturbed in the DDC induced liver injury model (Pandey et al., 2014). Reducing 5-HETE leads to mitigation of arsenic-induced NASH (Wei et al., 2020). These studies together support a pro-inflammatory role of 5-LOX and its metabolites during liver injury and a pro-growth role on hepatocytes (Figure 4).

Similar functions in liver disease and cancer have been reported for 12-LOX and 15-LOX (Tanaka et al., 2012; Xu et al., 2012; Ma et al., 2013; Yang et al., 2019). In HCV-HCC patient samples, both 12-HETE and 15-HETE are found elevated (Fitian et al., 2014). Deficiency of 12-LOX and 15-LOX activity attenuated steatosis, liver injury and inflammations observed in ApoE ^−/− mice (Martinez-Clemente et al., 2010). 12-HETE, the product of 12-LOX is found to be increased in plasma of NASH mice induced by MCD diet (Tanaka et al., 2012). Inhibiting 12-LOX activity attenuates HCC tumor cell growth and inhibits HFD promoted HCC development (Xu et al., 2012; Yang et al., 2019). 15-HETE production is disturbed in DDC treated mouse livers (Pandey et al., 2014). Reducing 15-HETE via inhibiting 15-LOX results in apoptosis (Ma et al., 2013). Similar to that of COX enzymes, PI3K-AKT signals are proposed to be involved in the cell survival/proliferation regulation by 12- and 15- LOX (Ma et al., 2013; Yang et al., 2019).

CYP enzymes are highly expressed in the liver. These enzymes are responsible for the vast majority of drug metabolism, but also play a significant role in xenobiotic elimination, where their dysfunction can lead to underlying liver diseases (Mukkavilli et al., 2014; Shoieb et al., 2020). Previous studies have established that etiologies such as ALD and cirrhosis have isoform specificities in their impact on CYP metabolism (Marino et al., 1998; Yang et al., 2003) with CYP2C and CYP2D being the most altered between healthy controls and liver disease cohorts (Frye et al., 2006). In HCC, Cyp enzymes responsible for PUFA metabolism have been identified among the top genes enriched in a study aimed at elucidating prognostic markers (Ding et al., 2022). This study also identified CYP26A1, CYP2C9 and CYP4F2 among a proposed prognostic panel of genes when trying to model the risks for iCCA and HCC (Ding et al., 2022). In a separate cohort, the expression of CYP2A6 was also closely associated with tumor grades and favorable prognosis (Jiang et al., 2021). In addition, several CYP4 enzymes are found to correlate with favorable outcomes for HCC and their protein expressions have been verified using immunohistochemical staining (Eun et al., 2018). Products of Cyp, such as 14,15-DHET have been found to correlate with liver cancer diagnosis marker alpha fetoprotein (AFP) in HBV-related HCC patient samples (Lu et al., 2018a) and NASH/fibrosis (Caussy et al., 2020). In cultured Huh7 cells, introduction of HCV core protein NS5A alters the expression of CYP2E1 (Smirnova et al., 2016). Together, these studies suggest that certain Cyp450 regulated oxylipins also play a role in promoting liver disease progression and cancer development.

Of the CYP produced oxylipins, 20-HETE is by far the most abundantly produced, accounting for 50%–75% of all Cyp450 eicosanoids produced in the liver and as such is one of the most characterized Cyp450 eicosanoids (Sacerdoti et al., 2003a). Analysis of cirrhosis cohorts has revealed elevated levels of 20-HETE as the predominant eicosanoids, even higher than that of PGs and TXs demonstrating the potential significance these eicosanoids have in liver disease progression (Sacerdoti et al., 1997; Li et al., 2023). Plasma levels of 20-HETE are also increased in NAFLD and alcoholic liver disease (ALD) patients among other proinflammatory oxylipins including 12-HETE and 8-HETE (Gao et al., 2019; Li et al., 2020a). In experimental models, 20-HETE has been shown to induce the activation of LX-2 cells via TGFβ signaling through proteasome regulation (Lai et al., 2018; Li et al., 2023) and inhibiting 20-HETE production attenuates liver fibrosis induced with CCL4 (Li et al., 2023). This effect may involve ubiquitination as 20-HETE decreases the expression of Nedd4-2 in the liver (Zhao et al., 2017).

Correlation studies have shown that EET levels are inversely correlated with NAFLD severity (Arvind et al., 2020). As steatosis progresses to fibrosis, epoxygenase activity significantly declines resulting in decreased EET levels. The oxylipin11,12-EET ameliorates free fatty acid induced inflammation through inhibition of NFκβ signaling in liver macrophages (Wang et al., 2019). The effect of biologically active EETs on vasoconstriction and inflammation maybe dependent on its ability to counteract that of 20-HETE which induces these effects (Lasker et al., 2000; Sacerdoti et al., 2003b). In experimental models, LPS decreases EET while increases 20-HETE (Anwar-mohamed et al., 2010; Theken et al., 2011). The importance of the 20-HETE/EET ratio is supported by studies using CYP4F2 transgenic mice (Zhang et al., 2016). In HCC, reduced expression of CYP2A6 modulates the anti-tumor immunity by disrupting the equilibrium between 20-HETE and EETs (Jiang et al., 2021).

In addition to the pro-inflammatory LTs produced from AA, 12-LOX, in conjunction with 15-LOX, plays a role in the synthesis of lipoxins such as LXA4 and LXB4 (Figure 2). In the liver, administration of LXA4 or treatment with BML-11, a lipoxin receptor agonist significantly improves hepatic injury and decreases fibrosis by reducing inflammatory cytokine release and attenuating hepatocyte apoptosis/necrosis in all liver injury models tested (Zhang et al., 2007; Xia et al., 2013; Zhou et al., 2013; El-Agamy et al., 2014; Zhang et al., 2015; Yan et al., 2016; Hu et al., 2017; Karaca et al., 2022). The effects of LXA4 are mediated via the renin angiotensin (RAS) system (Hu et al., 2017; Chen et al., 2019) and downregulation of NFκβ in hepatocytes and macrophages has been observed with LXA4 treatment (Kuang et al., 2016). In addition, LXA4 promotes apoptosis and inhibits cell proliferation and migration, and blocks EMT in HCC cells (Hao et al., 2011; Xu et al., 2018).

Since the 3-series PGs and 5-series of LTs produced from EPA and DHA are low-inflammatory lipids compared to those produced from AA metabolism (Li et al., 1994; Whelan et al., 1997), a lower ratio of EPA/AA is suggested to be a clinical sign of inflammation (Ebright et al., 2022). In ob/ob mice, supplementation of n-3 PUFAs attenuates hepatic steatosis (Gonzalez-Periz et al., 2006; Gonzalez-Periz et al., 2009). In the liver cancer model where PTEN loss drives steatosis and cancer (Stiles et al., 2004; He et al., 2016; Jia et al., 2017; Chen et al., 2021b), supplementation with a n-3 PUF, EPA, significantly attenuates both NASH and cancer development (Ishii et al., 2009). Supplementation with fish oil, the major dietary source for EPA and DHA antagonizes the production of AA-derived eicosanoids (Li et al., 1994) and also significantly ameliorates biochemical parameters observed in HCC induced by DEN treatment (Metwally et al., 2011). Together with the observation that RvD inhibits FOXM1 expression in CAFs and represses EMT and cancer stemness (Sun et al., 2019), a potential role of resolving lipids in regulating cancer stemness through PTEN-PI3K signaling maybe proposed.

Attenuation of GPCR and cAMP mediated signaling is associated with the anti-tumor effects observed with EPA and DHA (Smith et al., 2006), suggesting the involvement of eicosanoids, oxylipins and their receptor signaling in these effects. During the progression of NAFLD/NASH in HFD models, levels of RvD1 and MaR1 significantly decreases with disease progression (Maciejewska et al., 2020). Lower circulating levels of MaR1 and RvD1 were also reported for NAFLD/NASH patients (Monserrat-Mesquida et al., 2020; Fang et al., 2021). RvD1, MaR1 as well as RvE1 are found to regulate lipid biosynthesis in hepatocytes (Jung et al., 2014; Rius et al., 2017; Jung et al., 2018; Oh et al., 2022). In vivo, treatment with these SPMs led to reduced expression of FASn and ACC-1 and lower levels of liver TG (Laiglesia et al., 2018; Rodriguez et al., 2020; Zeng et al., 2022). During liver injury, these SPMs display a hepatoprotective effect (Figure 4) via attenuating the inflammatory responses, inhibiting hepatocyte apoptosis and oxidative stress (Murakami et al., 2011; Zhang et al., 2015; Kuang et al., 2016; Wang et al., 2016; Li et al., 2020b; Zhang et al., 2020b; Soto et al., 2020; Tang et al., 2021; Hardesty et al., 2023). In cultured hepatocytes, RvD1 also inhibits hepatocyte proliferation and is implicated in attenuating cancer growth (Lu et al., 2018b). Consistently, both RvD and RvE prevent the progression to cancer (Kuang et al., 2016; Rodriguez et al., 2020) and MaR treatment mitigated fibrosis induced by DEN (Rodriguez et al., 2021). Again, the AKT-mTOR regulated autophagy in HSC contributes to the RvD inhibited fibrosis (Li et al., 2021). Together, these studies suggest RvD and RvE antagonize the protumor cell growth signals from the tumor microenvironment (Figure 4). Finally, in primary hepatocytes, MaR transcriptionally regulates FGF21 (Martinez-Fernandez et al., 2019), of which the function is mimicked by the recently approved liver fibrosis therapy efruxifermin (Tillman et al., 2022). Together, these studies suggest a role of resolvins in tumor microenvironment signaling.

Macrophage functions can be defined by their polarization based on their cytokine production profiles in response to specific stimuli. The various degrees of polarization from M1 to M2 represent macrophage heterogeneity/reprogramming during the inflammatory responses. Tissues undergoing inflammatory response often harbor macrophages with both M1 and M2 polarizations. During liver injury, Kupffer cells are polarized to pro-inflammatory M1 phenotype in an effort to repair the tissue (Kang and Lee, 2016; Tu et al., 2020). Reprograming from M1 towards M2 phenotype is associated with resolution of inflammation and tissue regeneration. The bioactive lipids are implicated in this shifting of macrophage polarization from M1 towards M2 inflammatory phenotypes (Figure 5). This is evidenced by the altered macrophage polarization due to changes of dietary ratio of AA and EPA (Enos et al., 2015).

While often defined for their pro-inflammatory functions, eicosanoids also play a role in resolution of inflammation by promoting M2 polarization of macrophages. Liver macrophages from mice lacking PGES1 or treated with EP4 antagonist are polarized towards M1 inflammatory profiles (Nishizawa et al., 2018; Fang et al., 2021). In coculture systems using HCC cells, macrophages and T cells to mimic HCC microenvironment, M2 polarization is observed and found dependent on COX-2 expression (Xun et al., 2021). Thus, PGE2 production from macrophages appears to be associated with a M2 inflammatory state. These M2 polarized macrophages produce cytokines and growth factors that interacts with other cell types in the liver to drive the disease progression. For example, the M2 macrophages induces stellate cell (HSCs) autophagy to drive liver fibrosis (Cao et al., 2022). This process involves the production of PGE2 from the M2 macrophages and EP2 receptor that mediates the proliferation inhibition of the HSCs (Koide et al., 2004). Other proinflammatory eicosanoids have been shown to have opposite effects on HSCs (Pu et al., 2021; Li et al., 2023), though the involvement of macrophages were not explored. In the coculture system with macrophage, T-cells and hepatocytes, M2 polarized macrophages produce TGFβ to regulate T cell activity (Xun et al., 2021). Exhaustion of CD8⁺ T cell in this culture is caused by high COX-2-expressing HCC cell lines.

Consistent with an anti-inflammatory role of EPA produced eicosanoids, EPA-PC and EPA-PE reduce the elevated levels of serum TNF-alpha, IL-6 and MCP1 and attenuated macrophage infiltration in the liver (Wei et al., 2020). During liver injury, a proinflammatory condition is induced with decreasing M2 and increased M1 markers are observed in Kupffer cells (Kang and Lee, 2016). RvD attenuates these effects and leads to resolution of the proinflammatory conditions, while depletion of KCs by liposome clodronate abrogates this effects of RvD1 on proinflammatory mediators and macrophage polarization (Rius et al., 2014; Kang and Lee, 2016). Serving as a ligand for ROR, MaR1 also induces a M2 polarization in liver macrophages (Han et al., 2019). Together, these studies suggest both eicosanoids and pro-resolving oxylipins play roles in M2 macrophage polarization (Figure 5).

In addition to influencing macrophage polarization and cytokine production, the ability of macrophages to phagocytize apoptotic cells is also affected by eicosanoids. Efferocytosis, resulting from phagocytosis of engulfed apoptotic cells, particularly neutrophils, plays a key role in resolving underlying inflammation in liver disease. The unresolved inflammation and resulting chronic inflammation establish the immune tumor microenvironment for the development of HCC in the liver (Westbrook and Dusheiko, 2014; Fishbein et al., 2021; Heredia-Torres et al., 2022). While very little is known about the involvement of eicosanoids in efferocytosis of liver macrophages specifically, a role of eicosanoids in macrophages efferocytosis in general is well established (Thornton and Yin, 2021). In particular, SPMs are shown to be highly effective at promoting resolution of inflammation (Figure 6). Upon exposure to apoptotic cells, macrophages upregulate 5-LOX expression and enhances their ability to produce the pro-resolving SPMs including 15-HETE, 17-HDHA and RvD5 to participate in resolving inflammation (Snodgrass et al., 2021). The pro-resolving M2 macrophages prepared from human monocytes upregulate several resolvins include RvD, RvE and MaR and LXA4 and downregulate other pro-inflammatory eicosanoids including LTB4 to modulate their abilities to participate in efferocytosis (Dalli and Serhan, 2012). The pro-resolving lipoxins primarily exert their pro-resolving effects by binding to GPR32 on phagocytes and enhance their ability to phagocyte zymosan and apoptotic neutrophils (Krishnamoorthy et al., 2010). Due to the pro-resolving functions of LXA4 (Serhan et al., 1993), a stable LXA4 analogue, NAP1051 with a longer half-life has been developed (Dong et al., 2021). Like LXA4, this analogues inhibits neutrophil migration, and induce apoptosis of neutrophils, leading to a general resolving function.

During the phagocytic process, macrophages actively downregulate the production of cytokines including IL-1, IL-10, TNFα as well as LTC4 and TXB2 (Fadok et al., 1998). The production of PGE2, however, is increased in this process (Fadok et al., 1998). In several studies, blocking COX2 expression and PGE2 production is associated with reduced macrophage efferocytosis (Medeiros et al., 2009; Frasch et al., 2011; Salina et al., 2017; Sheppe and Edelmann, 2021; Ampomah et al., 2022). This function of PGE2 is thought to play a role in inflammation resolution during efferocytosis (Fadok et al., 1998; Takayama et al., 2002; Tang et al., 2012; Ampomah et al., 2022). Supporting this phagocytosis promoting role of PGE2, the phagocytosis ability of peritoneal and bone marrow derived macrophages is both attenuated in IBD mice carrying macrophage deletion of COX2 (Meriwether et al., 2022). In a zebra fish model, similar effects are observed (Loynes et al., 2018). However, here, PGE2 is shown to dose dependently drive neutrophilic inflammation resolution in the absence of macrophages (Loynes et al., 2018). Given the previous defined pro-inflammatory functions of PGE2, these effects of PGE2 on phagocytosis likely indicate a context-dependent role of PGE2 on inflammation and its resolution. The role of PGE2 in liver Kupffer cell phagocytosis and resolution of inflammation remain to be understood.