Ulcerative colitis is a chronic inflammatory bowel disease of multifactorial origin. The global incidence of UC is progressively increasing in recent decades, characterized by a chronic disease course and an associated risk of colon cancer, thus garnering escalating attention [1,2]. The occurrence and progression of UC are common side effects associated with the prolonged utilization of non-steroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, celecoxib, and meloxicam (Fig. 1) [[3], [4], [5]]. NSAIDs exerted their anti-inflammation effects through the nuclear factor kappa B (NF-κB) signaling pathway by non-selectively or selectively inhibiting cyclooxygenase (COX) enzymes, which play a pivotal role in the prostaglandin (PG) biosynthesis. Specifically, both COX-1 and COX-2 isoforms have been identified as critical targets for NSAID action [[6], [7], [8], [9]]. On one hand, COX-1 is an intrinsic isoenzyme ubiquitously expressed in various cell types, and prostaglandins synthesized by COX-1 exhibit gastroprotective effects [10]. Numerous clinical studies have reported that non-selective inhibition of COX-1, exemplified by diclofenac (Fig. 2), can lead to severe adverse effects, such as gastrointestinal and neurological damage [11,12]. On the other hand, concerns regarding the safety profiles of highly selective COX-2 inhibitors have arisen due to their association with cardiovascular diseases [13,14]. Furthermore, the presence of both COX-1 and COX-2 in normal tissues has been proven to play a superior physiological role in maintaining a balanced metabolism of prostaglandin, prostacyclin, and thromboxane A2 (TXA2) [[15], [16], [17]]. Recent findings also indicate that it is more favorable to maintain the functional balance between COX-1/COX-2 (IC50 (COX-1)/IC50(COX-2) = 5–50), considering the serious adverse effects associated with non-selective or highly selective COX-2 inhibitors [18,19].

COX-2 is the most thoroughly studied and best-understood mammalian dioxygenase. In addition to COX-2-NF-κB pathway, abundant previous reports have showed that multiply signal pathways play an essential role in the regulation of inflammatory response during UC, including mitogen-activated protein kinases (MAPK), and nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome [20,21]. NLRP3 induces inflammation through secretion of interleukin-1β (IL-1β), IL-18 and induction of pyroptosis. NF-kB activation precedes NLRP3 activation and enhances the expression of NLRP3 through the priming process. The research into drugs targeting the NLRP3 inflammasome pathway is currently experiencing a surge in the field of inflammatory diseases. The NLRP3 inflammasome pathway involves two key stages: priming and activation. The priming stage consists of transcriptional upregulation of NLRP3 and prointerleukin-1β (pro-IL-1β) through activation of NF-κB pathway. Next, NLRP3 is activated via one or more mechanisms, such as K+ efflux, lysosomal resident cathepsin B, and reactive oxygen species (ROS). Once NLRP3 becomes activated, there will be the activation of caspase-1 and exert regulatory role on the secretion of pro-inflammatory cytokine interleukin-1β (IL-1β), an important cytokine in innate immunity [22,23]. Recently, Lin et al. have reported that COX-2 can regulates the activation of NLPR3 inflammasome [24]. Furthermore, some studies have demonstrated that LPS activates MAPK/NF-κB/NLRP3 inflammasome signaling pathway, which in turn cause UC [25]. Hence, the inhibition of MAPK/NF-κB/NLRP3 inflammasome activation may contribute to reducing inflammation for the amelioration of UC.

Diclofenac, a non-selective COX-2 inhibitor, has been extensively utilized for the treatment of clinical inflammatory diseases. However, prolonged usage of diclofenac is associated with significant adverse effects such as exacerbation of gastric ulcers and an increased risk of gastrointestinal bleeding or active gastrointestinal ulcers [26]. Motivated by these findings, a rational design approach of diclofenac targeting COX-2/NLRP3 selective inhibition may represent a viable strategy to develop a potential anti-inflammatory lead compound with mitigated colitis-related adverse effects.