Ulcerative colitis (UC) belongs to inflammatory bowel disease (IBD), which is characterized by an uncontrolled inflammatory response, mucosal inflammation and ulceration [1]. Due to high relapse rate, serious complication, and high risk of developing colorectal cancer, UC poses serious threat to human health and is an economic burden to society [2,3]. Recent epidemiological data demonstrate a significant increase in the incidence of UC, leading to an urgent need for anti-UC drugs [4]. To date, several drugs including 5-aminosalicylic acid (5-ASA) [5], glucocorticoids [6], and immunosuppressants [7] have been utilized for the treatment of UC. However, these clinical drugs are limited due to their lack of specificity, high recurrence rates, and drug resistance, etc [8]. Thus, it is desirable to develop novel anti-UC agents with potent therapeutic efficacy.

Accumulating evidence demonstrates that the disruption of immune homeostasis is a critical factor in the pathogenesis of UC [[9], [10], [11]], especially intestinal T-cell dysfunction, which is characterized by Th17/Treg cells imbalance [12,13]. Th17 cells typically express the transcription factor retinoid-related orphan receptor (ROR)γt and secrete cytokines IL-17, IL-21, and IL-23, thereby triggering the inflammatory response. On the contrary, Treg cells conventionally secrete interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) to modulate the anti-inflammatory process [14]. Compared to healthy individuals or patients with UC in remission, the proportion of Th17 cells in the peripheral blood and colon mucosal tissue of active stage UC patients is significantly higher, while the proportion of Treg cells is lower [15]. Meanwhile, some research works report that reducing the production of proinflammatory cytokines and suppressing Th17 cell differentiation can slow down the progression of UC [[16], [17], [18]]. Therefore, remodeling the Th17/Treg balance is considered as an effective strategy for UC treatment.

Glycolysis is essential for glucose metabolism, providing energy for cell survival and proliferation [19]. Due to the fact that the proliferation and differentiation of Th17 cells are associated with the energy and substrates produced by glycolysis, inhibition of glycolysis can severely weaken Th17 cell differentiation. In glycolysis, pyruvate kinase isoform 2 (PKM2) is a key rate-limiting enzyme, which catalyzes the conversion of phosphoenolpyruvate (PEP) to pyruvate [20]. Recent studies have reported that PKM2 activators can suppress the proliferation of Th17 cell and the expression of IL-17A [[21], [22], [23]]. For example, the well-known PKM2 activators DASA-58 and TEPP-46 (Fig. 1), can stabilize PKM2 tetramers, inhibit PKM2 dimer translocation into the nucleus, and finally reduce the expression of IL-17 [24,25]. In addition, PKM2 is considered as a crucial factor in the occurrence and development of colitis. In 2019, Zen's research group reported that activating intestinal epithelial PKM2 can alleviate colitis [26]. Other research has revealed that SIRT5 desuccinylated and activated PKM2 blocking the production of IL-1β in macrophages and thereby preventing dextran sulfate sodium (DSS) induced colitis in mice [27]. Therefore, PKM2 is considered as a potential target for regulating the Th17/Treg balance, and the exploration of novel PKM2 activators for UC therapy has gained great attention.

There are many drug lead compounds that originate from natural products [28,29]. Saussurea costus, a traditional Chinese medicinal herb, is widely used to treat inflammatory and infectious disease [30]. Costunolide (Cos) is the main ingredient of Saussurea costus (content >2.84 %) and exhibits moderate anti-inflammatory activity [31]. In our previous study, Cos was found to ameliorate colitis by specifically inhibiting HIF-1α/glycolytic-mediated Th17 differentiation [32]. Subsequently, through structural optimization of Cos, the lead compound D5 was covalent-irreversibly interacted with Cys424 of PKM2, and demonstrated favorable protection effect on DSS and 2,4,6-trinitro-benzenesulfonic acid (TNBS) induced colitis [33]. Compared with Cos, the other natural product parthenolide (PTL), which has a similar gemmarane-type sesquiterpene lactone scaffold, is more abundant in the root bark of Magnolia delavayi (content >5 %) [34]. However, there have been no studies of PTL and its derivatives as PKM2 activators in the treatment of UC. Herein, with the expectation of discovering novel PKM2-activators as anti-UC agents, several PTL derivatives are designed and synthesized. Fortunately, though detailed structure optimization, compound B4 demonstrates excellent activate ability of PKM2 and anti-proliferative activity against T-cell in vitro, showing a favorable therapeutic effect on DSS-induced colitis in mouse model in vivo.