Pyroptosis is a novel kind of programmed cell death and Caspase-1 plays key roles in driving pyroptosis. The current study aims to elucidate the molecular mechanism affecting cardiomyocyte pyroptosis in myocardial ischemia/reperfusion (I/R) injury, both in vivo and in vitro.

A murine model of myocardial I/R injury was established and then treated with lentivirus-mediated shRNA targeting Caspase-1 to evaluate the effect of Caspase-1 on myocardial I/R injury. Further, Caspase-1 was silenced in the cardiomyocytes following hypoxia-reoxygenation (H/R) to detect the function of Caspase-1 in mitochondrial homeostasis and cardiomyocyte pyroptosis.

Knockdown of Caspase-1 inhibited the secretion of interleukin-1 beta (IL-1β), improved cardiac dysfunction and decreased pyroptosis in vivo. The cardio-protective effect was verified in the H/R-induced cardiomyocyte model. Recombinant IL-1β protein reversed the inhibitory effect of Caspase-1 knockdown on pyroptosis.

Overall, activating the Caspase-1/IL-1β axis by myocardial I/R injury causes mitochondrial homeostasis imbalance, pyroptosis, and the consequent cardiomyocyte injury.

JOURNAL/nrgr/04.03/01300535-202510000-00031/figure1/v/2024-11-26T163120Z/r/image-tiff Aminoglycosides are a widely used class of antibacterials renowned for their effectiveness and broad antimicrobial spectrum. However, their use leads to irreversible hearing damage by causing apoptosis of hair cells as their direct target. In addition, the hearing damage caused by aminoglycosides involves damage of spiral ganglion neurons upon exposure. To investigate the mechanisms underlying spiral ganglion neuron degeneration induced by aminoglycosides, we used a C57BL/6J mouse model treated with kanamycin. We found that the mice exhibited auditory deficits following the acute loss of outer hair cells. Spiral ganglion neurons displayed hallmarks of pyroptosis and exhibited progressive degeneration over time. Transcriptomic profiling of these neurons showed significant upregulation of genes associated with inflammation and immune response, particularly those related to the NLRP3 inflammasome. Activation of the canonical pyroptotic pathway in spiral ganglion neurons was observed, accompanied by infiltration of macrophages and the release of proinflammatory cytokines. Pharmacological intervention targeting NLRP3 using Mcc950 and genetic intervention using NLRP3 knockout ameliorated spiral ganglion neuron degeneration in the injury model. These findings suggest that NLRP3 inflammasome-mediated pyroptosis plays a role in aminoglycoside-induced spiral ganglion neuron degeneration. Inhibition of this pathway may offer a potential therapeutic strategy for treating sensorineural hearing loss by reducing spiral ganglion neuron degeneration.

Prolonged exposure to arsenic elevates the risk of developing a range of cardiovascular disorders. However, the mechanisms underlying myocardial damage from arsenic exposure remain elusive. Our earlier research suggest that drinking arsenic-contaminated water can lead to substantial inflammatory and necrotic injury in the myocardium of rats. This study was to ascertain whether mixed lineage kinase domain-like protein (MLKL) triggers Nod-like receptor protein-3 (NLRP3) activation during arsenic-induced myocardial necroinflammation in H9C2 cardiomyocytes and Mlkl knockout C57BL/6 mice. We demonstrated that arsenic exposure induces necroptosis by activating the receptor-interacting serine/threonine-protein kinase-3 (RIPK3)/MLKL pathway in vivo and in vitro. Consistent with our hypotheses, we found that necroptosis inhibitors (RIPK1 inhibitor necrostatin-1 [Nec-1], RIPK3 inhibitor [GSK-872], MLKL inhibitor [NSA]) and Mlkl genetic knockout can partially protect against arsenic-induced inflammatory damage. Additionally, these strategies can downregulate the expression of key proteins associated with the activation of the NLRP3 inflammasome, including NLRP3, Caspase-1, and interleukin-1β (IL-1β). Taken together, our findings demonstrate that MLKL triggers NLRP3 inflammasome activation and plays an essential role in arsenic-induced myocardial necroinflammation.

Early brain injury and delayed cerebral ischemia are combined intricate processes, and they represent the principal cause of subarachnoid hemorrhage (SAH)-related morbidity and mortality worldwide. Recent studies have shown that early lumbar CSF drainage can be used to decrease the incidence of delayed cerebral ischemia and improve long-term outcome. This approach has provided novel insights into post-SAH management that lessened the burden of secondary infarction and decreased the rate of unfavorable outcome. Given that the evaluation of this approach is contingent on prospective trial and early-stage randomized clinical trial, we review insights from studies that have elucidated the mechanisms underlying deterioration in SAH. We explore the role of iron homeostasis in the restoration of normal CSF circulation and the stabilization of optimal cerebral physiology to alleviate early brain injury and delayed neurologic impairment after SAH to advance the current understanding of SAH management.

Cerebral ischemia is a prevalent cerebrovascular disorder, with the restoration of blocked blood vessels serving as the current standard clinical treatment. However, reperfusion can exacerbate neuronal damage and neurological dysfunction, resulting in cerebral ischemia-reperfusion (I/R) injury. Presently, clinical treatment strategies for cerebral I/R injury are limited, creating an urgent need to identify new effective therapeutic targets. The PI3K/AKT signaling pathway, a pro-survival pathway associated with cerebral I/R injury, has garnered significant attention. We conducted a comprehensive review of the literature on the PI3K/AKT pathway in the context of cerebral I/R. Our findings indicate that activation of the PI3K/AKT signaling pathway following cerebral I/R can alleviate oxidative stress, reduce endoplasmic reticulum stress (ERS), inhibit inflammatory responses, decrease neuronal apoptosis, autophagy, and pyroptosis, mitigate blood-brain barrier (BBB) damage, and promote neurological function recovery. Consequently, this pathway ultimately reduces neuronal death, alleviates brain tissue damage, decreases the volume of cerebral infarction, and improves behavioral impairments. These results suggest that the PI3K/AKT signaling pathway is a promising therapeutic target for further research and drug development, holding significant potential for the treatment of cerebral I/R injury.

Cocoa tea (Camellia ptilophylla) is a popular beverage enjoyed worldwide, yet its protein-rich residues are often underutilized during processing. In this study, proteins from cocoa tea were extracted and hydrolyzed with alkaline protease to produce cocoa tea protein hydrolysates (CTPH). The results showed that CTPH exhibited promising anti-inflammatory activity. To uncover bioactive peptides, the hydrolysates were analyzed using UHPLC-MS/MS, and potential peptides were screened through molecular docking targeting the NLRP3 inflammasome. In an in vitro model of NLRP3 inflammasome activation, two active peptides, LLR and LIGF, were found to significantly reduce IL-1β production in PMA-differentiated THP-1 macrophages following treatment with nigericin or ATP. These peptides interact with the NACHT domain of NLRP3 via hydrogen bonding and hydrophobic interactions. Their binding to NLRP3 was further confirmed by CETSA assay. These findings suggest that cocoa tea-derived peptides could offer therapeutic potential for managing inflammation.

Atherosclerosis (AS) is a chronic inflammatory disease contributing to major cardiovascular events. This study aimed to investigate the effects of BAM15, a mitochondrial uncoupler, on regulating the NLRP3/ASC/caspase-1 signaling pathway to suppress endothelial cell pyroptosis and mitigate AS.

AS was induced in ApoE-/- mice through a high-fat diet (HFD), and the therapeutic effects of BAM15 (5 mg/kg/day, s. c.) were evaluated. Histological analyses, including HE staining and oil red O staining, were used to assess aortic pathology and lipid deposition. Serum inflammatory cytokines (IL-1β, IL-18) were quantified by ELISA. Mouse primary aortic endothelial cells (MAECs) were treated with oxidized low-density lipoprotein (ox-LDL) to simulate AS condition in vitro. Mitochondrial reactive oxygen species (mtROS) expression and oxidized (ox)-mtDNA content were detected by Mitosox staining and ELISA, respectively. Western blot was used to assess the expression of pyroptosis-related proteins, including GSDMD-NT, NLRP3, ASC, and cleaved-caspase-1.

BAM15 reduced atherosclerotic plaque formation, lipid deposition, and inflammation, and diminished mtROS expression and ox-mtDNA content in the AS mouse models. In both in vivo and in vitro experiments, BAM15 markedly inhibited the activation of the NLRP3 inflammasome, leading to reduced pyroptosis in endothelial cells. Activation of the NLRP3/ASC/caspase-1 signaling pathway by Nigericin partially reversed the protective effects of BAM15, underscoring the pivotal role of NLRP3 inflammasome inhibition in endothelial pyroptosis suppression.

BAM15 effectively inhibits endothelial cell pyroptosis by reducing mtROS production and ox-mtDNA release to suppress the NLRP3/ASC/caspase-1 signaling pathway, thereby alleviating AS in both in vivo and in vitro models.

Diminished ovarian reserve (DOR) is a major cause of infertility, often triggered by inflammation and oxidative stress. Pyroptosis, a form of programmed cell death, has been implicated in DOR pathogenesis. Itaconic acid (IA), an endogenous metabolite, is known for its anti-inflammatory and antioxidant properties. This study aimed to explore whether IA could alleviate lipopolysaccharide (LPS)-induced DOR in mice by inhibiting pyroptosis through the NRF2 pathway.

A DOR mouse model was established by administering LPS for 5 consecutive days, followed by IA treatment. Ovarian function was assessed by follicle count and hormone levels. Inflammatory markers, oxidative stress, and pyroptosis-related proteins were evaluated in both in vivo and in vitro models. The molecular mechanism was further investigated using inhibitors and molecular docking studies.

IA significantly improved ovarian function in LPS-induced DOR mice by increasing the number of follicles and normalizing hormone levels. IA also reduced inflammation, oxidative stress, and pyroptosis, as evidenced by lower expression of NLRP3, cleaved-caspase-1, and N-GSDMD, while increasing NRF2 expression. In vitro, IA enhanced granulosa cell (GC) viability, reduced reactive oxygen species (ROS), and decreased pyroptosis in LPS-treated GCs. Additionally, the beneficial effects of IA were mediated via the NRF2 pathway, as NRF2 inhibition (ML385) reversed these improvements. Additionally, we identified GSDMD as a downstream target of IA, with inhibition of GSDMD ameliorating DOR progression and inflammatory responses.

IA alleviates LPS-induced DOR by reducing inflammation, oxidative stress, and pyroptosis through activation of the NRF2 signaling and direct inhibition of the GSDMD pathway. These findings suggest that IA may serve as a potential therapeutic agent for improving ovarian reserve and fertility.

Stroke poses a threat to the elderly, being the second leading cause of death and the third leading cause of disability worldwide. Ischemic stroke (IS), resulting from arterial occlusion, accounts for ~85% of all strokes. The pathophysiological processes involved in IS are intricate and complex. Currently, tissue plasminogen activator (tPA) is the only Food and Drug Administration‑approved drug for the treatment of IS. However, due to its limited administration window and the risk of symptomatic hemorrhage, tPA is applicable to only ~10% of patients with stroke. Additionally, the reperfusion process associated with thrombolytic therapy can further exacerbate damage to brain tissue. Therefore, a thorough understanding of the molecular mechanisms underlying IS‑induced injury and the identification of potential protective agents is critical for effective IS treatment. Over the past few decades, advances have been made in exploring potential protective drugs for IS. The present review summarizes the specific mechanisms of various forms of programmed cell death (PCD) induced by IS and highlights potential protective drugs targeting different PCD pathways investigated over the last decade. The present review provides a theoretical foundation for basic research and insights for the development of pharmacotherapy for IS.

Aberrant activation of the NLRP3 inflammasome is critically involved in sepsis-induced acute lung injury (ALI), with inhibition of this pathway emerging as a promising therapeutic approach. This study identifies Dipyridamole, an FDA-approved drug, as a novel inhibitor of the NLRP3 inflammasome. Mechanistically, Dipyridamole suppresses mitochondrial ROS release and directly interacts with NEK7, thereby preventing its association with NLRP3 and impeding inflammasome complex assembly. In an LPS-induced sepsis model, Dipyridamole significantly ameliorated ALI, reduced inflammatory responses, and improved survival rates in model mice. Additionally, Dipyridamole effectively inhibited NLRP3 inflammasome activation in lung tissue. These findings position Dipyridamole as a potent NLRP3 inflammasome inhibitor with substantial therapeutic potential for managing sepsis-induced ALI.

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a critical player in cancer pathogenesis. Concurrently, inflammation, a key biological response to tissue injury or infection, significantly influences cancer development and progression. The interplay between ferroptosis and inflammation represents a promising yet underexplored area of research. This review synthesizes recent advances in understanding the molecular mechanisms governing their interaction, emphasizing how ferroptosis triggers inflammatory responses and how inflammatory mediators, such as TNF-α, regulate ferroptosis through iron metabolism and lipid peroxidation pathways. Key molecular targets within the ferroptosis-inflammation axis, including GPX4, ACSL4, and the NF-κB signaling pathway, offer therapeutic potential for cancer treatment. By modulating these targets, it may be possible to enhance ferroptosis and fine-tune inflammatory responses, thereby improving therapeutic outcomes. Additionally, this review explores the broader implications of targeting the ferroptosis-inflammation interplay in disease treatment, highlighting opportunities for developing innovative strategies to combat cancer. By bridging the gap in current knowledge, this review provides a comprehensive resource for researchers and clinicians, offering insights into the therapeutic potential of this intricate biological relationship.

Radiation therapy (RT) remains an essential treatment modality for lung cancer, yet its effectiveness is frequently hindered by radiation-induced lung injury (RILI), a common outcome of modern therapeutic regimens. With the aim of addressing this challenge, a novel nanocomposite, Au@mSiO2@Mn(CO)5Br (ASMB), was synthesized with Au@mSiO2 as the carrier and Mn(CO)5Br as the functional component. The gold nanorods (Au rods) core generates reactive oxygen species (ROS) under X-ray irradiation, which then activates Mn(CO)5Br to release carbon monoxide (CO) locally within the lung during radiotherapy. The released CO then diffuses to surrounding tissues, inhibiting the excessive accumulation of ROS, thereby preventing damage to normal cells caused by ROS generated in a short period of time. Meanwhile, the released manganese ions (Mnn+) catalyze the conversion of hydrogen peroxide (H2O2) in the microenvironment into oxygen (O2). In vitro experiments demonstrated that the release of CO markedly attenuated radiation-induced ROS production, thereby inhibiting the activation of the NLRP3 inflammasome and reducing the levels of inflammatory cytokines and pyroptosis-related proteins. Moreover, it downregulated the expression of fibrosis-associated proteins, including TGF-β1 and α-SMA. Additionally, CO facilitated DNA damage repair, thereby mitigating radiation-induced tissue injury. In the RILI model, the ASMB NPs-treated lungs exhibited notably reduced pulmonary edema, congestion, and inflammatory cell infiltration, primarily by inhibiting NLRP3 inflammasome-dependent pyroptosis and reducing levels of inflammation and fibrosis markers. The release of O2 further mitigates local tissue hypoxia, enhancing the effectiveness of radiotherapy. Overall, ASMB NPs provide a promising alternative for the treatment of RILI and a potential therapeutic strategy to improve the efficacy of radiotherapy.

Activation of NOD-like receptor protein 3 (NLRP3) can lead to the production of inflammatory factors and perturbation of macrophage polarization, leading to an intestinal immune imbalance that promotes the progression of ulcerative colitis (UC). In this study, we investigated the therapeutic effect of Kurarinone and Nor-kurarinone on UC and their regulatory mechanisms relating to NLRP3 inflammasome activation and macrophage polarization. UC mice were induced using dextran sulfate sodium (DSS) and treated with Kurarinone and Nor-kurarinone. Results showed that Kurarinone and Nor-kurarinone could alleviate weight loss, decrease the disease activity index (DAI) score, shorten colon length, inhibit formation of the NLRP3 inflammasome in the colon and regulate macrophage polarization in UC mice. The THP-1 cells were used as an in vitro model of the NLRP3 inflammasome, conducted by treatment with lipopolysaccharide (LPS) and ATP/Nigericin. Kurarinone and Nor-kurarinone can inhibit the NLRP3 inflammasome formation response by disrupting the NLRP3/ASC interaction to inhibit NLRP3 assembly and then regulating the polarization of macrophages. In conclusion, Kurarinone and Nor-kurarinone inhibited NLRP3 inflammasome assembly to counteract activation of the NLRP3 inflammasome. This inhibition led to a reduction in M1 polarization of intestinal macrophages in UC mice to keep the balance of M1/ M2 macrophages. Our study suggests that Kurarinone and Nor-kurarinone may be novel therapeutic modalities for UC.

Chlorpyrifos (CPF), a toxic organophosphorus insecticide, is widely used in agriculture to protect crops (eg., maize) from pests. The use of CPF in crops can result in accumulation in crop seeds, such as corn seeds, which is a primary feed ingredient in pigs. Pigs in China, which is an important source of animal-derived protein in the Chinese diet, account for over 50 % of the raised pig population in the whole world. Therefore, CPF may pose a potential risk to the health of non-target organisms (pigs and humans) through the food chain. However, whether CPF can damage porcine intestine remains unknown. Selenium (Se), an essential trace element, was reported to have antioxidant and anti-toxic effects. Tight junction (TJ) is an important mechanism of intestinal injury and pyroptosis is a new hotspot in the field of toxicology. Hence, we wanted to investigate whether CPF can damage pig intestine and whether selenium nanoparticles (SeNPs) supplement can alleviate CPF-induced pig intestine damage, and to study corresponding mechanism from the three aspects of OS, pytoptosis, and TJ. We established a model of SeNPs alleviating damage caused by CPF in intestinal porcine enterocytes (IPEC-J2 cells), and found that SeNPs alleviated CPF-induced oxidative stress (OS), pyroptosis, and intestinal barrier dysfunction in IPEC-J2 cells. Interestingly, OS, pyroptosis, and intestinal barrier dysfunction had serial relations, and ROS/Nrf2/Caspase-1/Occludin and ROS/Nrf2/Caspase-1/ZO-1 pathways played a role. Notably, ROS and Caspase-1 played an initial and important role, respectively. Our study added new information on pesticides-caused damage to non-target organisms, and provided new idea, insight, and targets to mitigatie pesticides-induced toxic effect on non-target organisms.

The nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, discovered 20 years ago, is crucial in controlling innate immune reactions in Alzheimer's disease (AD). By initiating the release of inflammatory molecules (including caspases, IL-1β, and IL-18), the excessively activated inflammasome complex in microglia leads to chronic inflammation and neuronal death, resulting in the progression of cognitive deficiencies. Even though the involvement of NLRP3 has been implicated in neuroinflammation and widely explored in several studies, there are plenty of controversies regarding its precise roles and activation mechanisms in AD. Another prominent feature of AD is impairment in microglial autophagy, which can be either the cause or the consequence of NLRP3 activation and contributes to the aggregation of misfolded proteins and aberrant chronic inflammatory state seen in the disease course. Studies also demonstrate that intracellular buildup of dysfunctional and damaged mitochondria due to defective mitophagy enhances inflammasome activation, further suggesting that restoration of impaired autophagy and mitophagy can effectively suppress it, thereby reducing inflammation and protecting microglia and neurons. This review is primarily focused on the role of NLRP3 inflammasome in the etiopathology of AD, its interactions with microglial autophagy/mitophagy, and the latest developments in NLRP3 inflammasome-targeted therapeutic interventions being implicated for AD treatment.

This study aimed to explore the potential preventive effects of fudosteine (Fud) on PM2.5-induced asthma exacerbations in a murine model. BALB/c mice were randomly allocated into six groups: control, Fud, ovalbumin (OVA), OVA+Fud, OVA+PM2.5, and OVA+PM2.5 + Fud. An asthma model was established through OVA sensitization and challenge. Compared to the OVA group, PM2.5 exposure exacerbated allergic asthma, as evidenced by increased collagen fiber deposition, goblet cell metaplasia, mucus secretion, heightened airway inflammation, elevated total cell and eosinophil counts, and upregulated levels of interleukin (IL)-1β, IL-18, and NLRP3 expression in lung tissues. Notably, fudosteine treatment mitigated these pathological changes. Western blot analysis revealed that fudosteine significantly reduced the expression of NLRP3, caspase-1, gasdermin D (GSDMD), cleaved-caspase-1, and cleaved-GSDMD in lung tissues. In conclusion, fudosteine alleviated lung inflammation, collagen deposition, and mucus secretion in PM2.5-induced asthma exacerbation, potentially by inhibiting the NLRP3 inflammasome-mediated pyroptosis pathway.

Over the past decade, significant advances have been made in our understanding of how NACHT-, leucine-rich-repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasomes are activated. These findings provide detailed insights into the transcriptional and posttranslational regulatory processes, the structural-functional relationship of the activation processes, and the spatiotemporal dynamics of NLRP3 activation. Notably, the multifaceted mechanisms underlying the licensing of NLRP3 inflammasome activation constitute a focal point of intense research. Extensive research has revealed the interactions of NLRP3 and its inflammasome components with partner molecules in terms of positive and negative regulation. In this Review, we provide the current understanding of the complex molecular networks that play pivotal roles in regulating NLRP3 inflammasome priming, licensing and assembly. In addition, we highlight the intricate and interconnected mechanisms involved in the activation of the NLRP3 inflammasome and the associated regulatory pathways. Furthermore, we discuss recent advances in the development of therapeutic strategies targeting the NLRP3 inflammasome to identify potential therapeutics for NLRP3-associated inflammatory diseases. As research continues to uncover the intricacies of the molecular networks governing NLRP3 activation, novel approaches for therapeutic interventions against NLRP3-related pathologies are emerging.

Few studies have examined the mechanisms underlying the development of trigeminal neuralgia involving the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3). The purpose of this experiment was to investigate the role of NLRP3 in the antinociceptive effects of botulinum toxin type A (BTX-A) in trigeminal neuralgia. We used a trigeminal neuralgia animal model induced by injecting 1-acyl-2-lyso-sn-glycero-3-phosphate (LPA) into the trigeminal nerve root of rats. Rats treated with LPA showed a significant increase in the expression of NLRP3 in the trigeminal ganglion 9 days after LPA injection. Furthermore, the levels of interleukin (IL)-1β, IL-18, and tumor necrosis factor (TNF)-α increased on postoperative day 9. Subcutaneous administration of BTX-A (3 U/kg) in the vibrissa pad resulted in a significant attenuation of mechanical allodynia, and the antiallodynic effects lasted for 7 days. The upregulated NLRP3 expression in the trigeminal ganglion was suppressed 2 days after the injection of BTX-A. Moreover, the BTX-A injection significantly reduced the concentrations of IL-1β, IL-18, and TNF-α in the trigeminal ganglion. Intraganglionic injection of an NLRP3 inhibitor blocked mechanical allodynia and attenuated the upregulated cytokine concentrations in the LPA-treated rats. These results indicate that BTX-A induces its antinociceptive effects in the LPA-induced trigeminal neuralgia animal model by attenuating the NLRP3-cytokine pathway in the trigeminal ganglion.

Streptococcus equi subsp. zooepidemicus (SEZ) is an important pathogen which is responsible for a wide range of diseases in various species. Macrophages are professional phagocytes that can engulf microorganisms and trigger responses leading to microbial death. Caspase-1 is considered as a proinflammatory factor that mediates antibacterial response to protect hosts from bacteria. Here, we revealed a novel role of Caspase-1 in mice against SEZ. Through both in vitro and in vivo infection assays, we demonstrated that the maturation and secretion of the cytokine IL-1β are critically dependent on Caspase-1 activation. The Caspase-1 deficient mice displayed attenuation of bactericidal activity against SEZ, mainly by decreasing the accumulation of macrophage. In addition to the recruitment of macrophages, deficiency of Caspase-1 also impaired the phagocytosis of SEZ by macrophages. Our study demonstrated that Caspase-1 is critical for mice to defense against SEZ depending on the recruitment and phagocytosis of macrophage.

Intestinal ischemia‑reperfusion (IIR) injury is caused by the restoration of blood supply after a period of ischemia. It occurs in numerous clinical pathologies, such as intestinal obstruction, incarcerated hernia and septic shock, with mortality rates of 50‑80%. Honokiol (HKL), isolated from the herb Magnolia officinalis, is a biphenolic natural product with antioxidative, antibacterial, antitumor and anti‑inflammatory properties. Additionally, HKL has protective effects in ischemia‑reperfusion injuries, but its role and specific mechanisms in IIR injury are yet to be elucidated. In the present study, the superior mesenteric artery was ligated in rats to establish an IIR model. Hematoxylin and eosin staining and ELISA revealed that HKL administration ameliorated IIR‑induced injury in rats, which was demonstrated by a reduced destruction to the intestinal mucosa, as well as a reduced serum intestinal fatty acid‑binding protein concentration and Chiu's score in 10 mg/kg HKL treated IIR‑induced rats compared with those without HKL treatment. Additionally, immunohistochemical (IHC) staining and western blotting revealed that the occludin and tight junction protein 1 protein levels were increased in the 10 mg/kg HKL treated IIR‑induced rats compared with those without HKL treatment. Furthermore, an in vitro hypoxia/reoxygenation (H/R) cell model was established using IEC‑6 cells. Cell Counting Kit‑8 and lactate dehydrogenase (LDH) assays indicated that HKL mitigated the H/R‑inhibited cell viability and decreased the LDH levels in cell supernatants. Mechanistically, immunofluorescent (IF) staining and western blotting revealed that HKL inhibited H/R‑triggered pyroptosis. Furthermore, Mito‑Tracker, mitochondrial membrane potential and MitoSOX staining as well as western blotting revealed that reducing mitochondrial reactive oxygen species (ROS) inhibited the H/R‑induced pyroptosis by mitigating mitochondrial dysfunction. In the present H/R cell model, HKL improved the mitochondrial function by increasing the expression of sirtuin 3 (SIRT3), while IF staining and western blotting indicated that silencing SIRT3 notably reduced the beneficial effect of HKL on pyroptosis. In addition, IHC staining and western blotting revealed that HKL treatment mitigated the IIR‑induced pyroptosis in rats. Therefore, HKL treatment may mitigate IIR‑induced mitochondrial dysfunction and reduce mitochondrial ROS production by increasing the expression of SIRT3 protein, potentially resulting in an inhibition of pyroptosis during IIR.

In the present study, a new type of Caspase-1 homolog is identified from Crassostrea gigas (defined as CgCas1-2D). It is composed of 2×DSRM-CASc domain and has closer evolutionary relationship with mammalian Caspase-1s. The mRNA expressions of CgCas1-2D increase significantly after Vibrio splendidus or LPS stimulation. Recombinant CgCas1-2D and its 2×DSRM and CASc domains all bind various PAMPs and bacteria. rCgCas1-2D shows the highest binding activity to human Caspase-1 substrate. Upon recognizing bacteria, CgCas1-2D co-localizes and interacts with CgGSDME, while it has no cleavage activity to CgGSDME. CgCas1-2D inhibits the histone methylation and acetylation levels and CgNF-κB/Rel nuclear translocation mediated by CgGSDME. In addition, CgCas1-2D suppresses the mRNA expression levels of cytokines mediated by GSDME-NF-κB/Rel axis. The results demonstrate that a new type of anti-inflammatory Caspase-1 identified from oyster upon recognizing various bacteria interacts with GSDME to inhibit the histone modification and NF-κB signaling to suppress the inflammation.

The canonical complement-mediated lysis of mature red blood cells (RBCs) leads to severe pathogenesis. However, inhibition strategies targeting complement are not always as efficient as expected, indicating that unknown mechanisms are awaiting elucidation. In this study, we investigate the intracellular events in mature RBCs following complement activation. The collected evidence demonstrates that complement-induced hemolysis is a caspase-8-dependent programmed RBC death. Furthermore, short NLRP3 (miniNLRP3) fragments in RBCs are identified to engage in the assembly of NLRP3-apoptosis-associated speck-like protein containing a CARD (ASC)-caspase-8 complex. Activated caspase-8 directly induces the proteolysis of β-spectrin, thereby disrupting the skeletal network of the RBC membrane, a process we refer to as spectosis. Spectosis signaling is also activated in autoimmune hemolytic anemia or paroxysmal nocturnal hemoglobinuria, and the inhibition of spectosis significantly reduced complement-induced hemolysis. These findings reveal a programmed death cascade in mature RBCs, which may have important implications for the treatment of hemolytic disorders.

Thymic epithelial cells (TECs) are critical for thymic structure and function, yet the impact of T-2 toxin (T-2) on TECs and related molecular pathways remains unclear. This study sheds light on the mechanisms of T-2-induced TEC damage, focusing on the ROS-NF-κB-NLRP3 signaling axis. The in vivo and in vitro analyses suggest that T-2 induces TEC injury through ROS-driven NLRP3 inflammasome activation, NF-κB signaling, inflammation, and apoptosis. Molecular docking analysis verified the binding of T-2 to critical components involved in oxidative stress, inflammatory signaling pathways, and apoptosis. These findings were further supported by therapeutic interventions targeting ROS and NLRP3. N-acetylcysteine (NAC) effectively reduced ROS levels, suppressed NF-κB signaling, inhibited NLRP3 activation, and mitigated inflammation and apoptosis, effects mirrored by the NLRP3 inhibitor MCC950, emphasizing the critical role of ROS-mediated NLRP3 inflammasome activation through NF-κB signaling in T-2-induced TEC damage. Concurrently, inhibition of the NF-κB signaling further suppressed ROS levels, NLRP3 inflammasome activation, and apoptosis in MTEC1 cells, emphasizing the pivotal function of the ROS-NF-κB-NLRP3 axis in the pathogenesis of T-2-induced thymic injury. Our study offers an in-depth insight into the mechanisms driving T-2-induced immunotoxicity and identifies potential therapeutic strategies targeting these pathways to mitigate thymic injury and preserve immune function.

Parkinson's disease (PD), a progressive neurodegenerative disorder, is characterized by the loss of dopaminergic neurons and pathological aggregation of α-synuclein (α-Syn). Emerging evidence highlights the interplay between genetic susceptibility, neuroinflammation, and transcriptional dysregulation in driving PD pathogenesis. This review brings together the latest information on three important players: α-Syn, the transcription factor Orphan nuclear receptor (NURR1), and the NOD-like receptor 3 (NLRP3) inflammasome. Pathogenic α-syn aggregates cause damage to neurons by disrupting mitochondria and lysosomes and spreading in a way similar to prion proteins. They also turn on the NLRP3 inflammasome, which is a key player in neuroinflammation. NLRP3-driven release of pro-inflammatory cytokines exacerbates neurodegeneration and creates a self-sustaining inflammatory milieu. Meanwhile, reduced NURR1 activity, a pivotal modulator of dopaminergic neuron survival and development, exposes neurons to oxidative stress, neuroinflammation, and α-Syn toxicity, hence exacerbating disease progression. So, targeting this trio exhibits transformative potential against PD pathogenesis.

Pyroptosis at the maternal-fetal interface plays an important role in fetal growth restriction development. hsa_circ_0081343 can be an RNA-binding protein "sponge" regulating Rbm8a nuclear transportation through binding to Rbm8a. This study aimed to elucidate the regulatory mechanism underlying the interaction between hsa_circ_0081343 and Rbm8a in the FGR pyroptosis pathway.

The expression levels of PI3K/AKT pathway-related components (PI3K, AKT, p-PI3K, and p-AKT), HIF-1α, NLRP3, and proinflammatory cytokines (IL-1β, IL-6, and TNF-α) were measured using RT-qPCR, Western blot, and ELISA. RNA-seq and ChIP-seq were used to identify the downstream signaling pathways of hsa_circ_0081343 and Rbm8a in HTR8-SVneo. RNA pull-down assays, Western blot, and RT-qPCR were performed to investigate the interactions between hsa_circ_0081343 and Rbm8a.

The placenta of FGR exhibited considerable upregulation of NLRP3 compared to normal controls. Overexpression of hsa_circ_0081343 inhibited pyroptosis and subsequent inflammatory responses in HTR-8/SVneo cells, and these effects were reversed by Rbm8a knockdown. The integration of RNA-seq and ChIP-seq showed that the PI3K/AKT and HIF-1α pathways were the targets of hsa_circ_0081343 and Rbm8a. hsa_circ_0081343 upregulation and Rbm8a downregulation was accompanied by the inhibition of the PI3K/AKT/HIF-1α signaling pathway, whereas hsa_circ_0081343 knockdown of and Rbm8a overexpression led to the opposite effect. Moreover, Rbm8a binds to hsa_circ_0081343, flanking the intron sequence. Rbm8a overexpression significantly decreased hsa_circ_0081343 expression.

These results indicated that the interaction between hsa_circ_0081343 and Rbm8a regulates NLRP3-mediated pyroptosis through the PI3K/AKT/HIF-1α signaling pathway. Furthermore, Rbm8a binds to hsa_circ_0081343, flanking the intron sequence and modulating hsa_circ_0081343 formation. Our results provide a new direction for further exploration of the regulatory mechanisms of circRNA-RBPs in the pathogenesis of FGR.

A substance integral to the sustenance and functionality of virtually all forms of life is manganese (Mn), classified as an essential trace metal. Its significance lies in its pivotal role in facilitating metabolic processes crucial for survival. Additionally, Mn exerts influence over various biological functions including bone formation and maintenance, as well as regulation within systems governing immunity, nervous signaling, and digestion. Manganese nanoparticles (Mn-NP) stand out as a beacon of promise within the realm of immunotherapy, their focus honed on intricate mechanisms such as triggering immune pathways, igniting inflammasomes, inducing immunogenic cell death (ICD), and sculpting the nuances of the tumor microenvironment. These minuscule marvels have dazzled researchers with their potential in reshaping the landscape of cancer immunotherapy - serving as potent vaccine enhancers, efficient drug couriers, and formidable allies when paired with immune checkpoint inhibitors (ICIs) or cutting-edge photodynamic/photothermal therapies. Herein, we aim to provide a comprehensive review of recent advances in the application of Mn and Mn-NP in the immunotherapy of cancer. We hope that this review will display an insightful view of Mn-NPs and provide guidance for design and application of them in immune-based cancer therapies.

Background/Objectives: Metabolic-dysfunction-associated steatotic liver disease (MASLD) progresses from hepatic steatosis to hepatocellular carcinoma (HCC) as a result of systemic immunometabolic dysfunction. This review summarizes the key roles of the innate and adaptive immune mechanisms driving hepatic injury, fibrogenesis, and carcinogenesis in MASLD. Methods: A comprehensive literature review was performed using PubMed to identify relevant published studies. Eligible articles included original research and clinical studies addressing immunological and metabolic mechanisms in MASLD, as well as emerging therapeutic strategies. Results: We highlight the roles of cytokine networks, the gut-liver axis, and immune cell reprogramming. Emerging therapeutic strategies, including cytokine inhibitors, anti-fibrotic agents, metabolic modulators, and nutraceuticals, offer several indications for attenuating MASLD progression and reducing the prevalence of extrahepatic manifestations. Conclusions: Given the heterogeneity of MASLD, personalized combination-based approaches targeting both inflammation and metabolic stress are essential for effective disease management and the prevention of systemic complications.

Background: Glycocalyx disintegration is associated with adverse outcomes in patients with trauma or sepsis. As microvascular dysfunction has an impact on disease progression in chronic heart failure (CHF) patients, we hypothesized that changes in microcirculation might be associated with mortality. Methods: Fifty patients with ischemic and non-ischemic cardiomyopathy and conservative treatment with baseline measurements of the sublingual microcirculation (via Sidestream Darkfield videomicroscopy) were followed up for two years. Glycocalyx thickness was assessed indirectly by calculation of the perfused boundary region (PBR). Results: Loss of glycocalyx was pronounced in non-survivors after one, n = 10, and two years, n = 16; PBR: 2.05 μm (1.88-2.15 μm) vs. 1.87 μm (1.66-2.03 μm) and 2.04 (1.93-2.11) vs. 1.84 (1.62-1.97); p = 0.042 and p = 0.003, respectively. Area under the ROC curve for the analysis of the predictive value of PBR on two-year mortality was 0.77 (p = 0.003; SE: 0.07, CI (95%): 0.63-0.91). ROC curve analysis determined a PBR of 1.9 μm as the best predictor for two-year mortality (sensitivity: 0.81; specificity: 0.59). Moreover, multivariate regression analysis revealed PBR and functional capillary density as significant predictors of two-year mortality, p = 0.036 and p = 0.048, respectively. Conclusions: Glycocalyx disintegration is related to poor overall survival in CHF patients.

Diabetic encephalopathy (DE) is a neurological complication characterized by neuroinflammation, cognitive impairment, and memory decline, with its pathogenesis closely linked to the activation of the NLRP3 inflammasome. As a central regulator of the innate immune system, the NLRP3 inflammasome plays a pivotal role in DE progression by mediating neuroinflammation, pyroptosis, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum (ER) stress, and microglial polarization. This review systematically explores the molecular mechanisms by which the NLRP3 inflammasome contributes to DE, focusing on its role in neuroinflammatory cascades and neuronal damage, as well as the diabetes-associated physiological changes that exacerbate DE pathogenesis. Furthermore, we summarize emerging therapeutic strategies targeting the NLRP3 inflammasome, including small-molecule inhibitors and bioactive compounds derived from traditional herbal medicine, highlighting their potential for DE treatment. These findings not only advance our understanding of DE but also provide a foundation for developing NLRP3-targeted pharmacological interventions.

Atherosclerosis (AS) is a chronic inflammatory disease characterized by the gradual accumulation of plaques in arterial walls, with its pathogenesis remaining incompletely understood. Recent studies have highlighted that development of AS is closely associated with the aberrant activation of the NLRP3 inflammasome in the arteries. Inhibition of the NLRP3 inflammasome by natural products and formulae derived from Chinese herbal medicines (CHMs) has been shown to alleviate AS-associated pathologies. However, therapies that effectively and safely target the NLRP3 inflammasome remain limited. This review aims to summarize the key discoveries from recent studies on the effects of these natural products and formulae on the NLRP3 inflammasome in the context of AS treatment. A comprehensive literature search was conducted on databases such as PubMed/MEDLINE up to January 2025, yielding 38 eligible studies. Our analysis indicates that certain therapies can effectively prevent arterial inflammation in animal models by targeting multiple pathways and mechanisms related to the NLRP3 inflammasome. This review summarizes the primary findings of these studies, focusing on the therapeutic effects and underlying mechanisms of action. Based on these insights, we propose future strategies to enhance the efficacy, specificity, and safety of existing natural products and formulae for AS treatment. Additionally, this study offers a perspective for future research that may enhance our understanding of the roles and the mechanisms of CHM-derived phytochemicals and formulae in regulating the NLRP3 inflammasome and treating AS.

Intestinal ischemia-reperfusion injury (II/RI) is a critical acute condition characterized by complex pathological mechanisms, including various modes of cell death. Among these, pyroptosis has garnered significant attention in recent years. This review explores the characteristics, molecular mechanisms, and implications of pyroptosis in II/RI, with a focus on therapeutic strategies targeting the pyroptosis pathway. Key processes such as NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation, caspase-1 activation, and gasdermin D (GSDMD)-mediated membrane pore formation are identified as central to pyroptosis. Compounds like MCC950, CY-09, metformin, and curcumin have shown promise in attenuating II/RI in preclinical studies by modulating these pathways. However, challenges remain in understanding non-canonical pyroptosis pathways, unraveling the exact mechanisms of GSDMD-induced pore formation, and translating these findings into clinical applications. Addressing these gaps will be crucial for developing innovative and effective treatments for II/RI.

The pathology of early MIRI (myocardial ischemia/reperfusion injury) is characterized by sterile inflammation. TRPV1 (transient receptor potential vanilloid 1) and NLRP3 inflammasome sense harmful stimulation and modulate inflammation in cardiomyocytes. We recently demonstrated morphine downregulated p-TRPV1 and exacerbated MIRI. In this study, we investigate the potential crosstalk of TRPV1 and NLRP3 inflammasome activities and a potential modulatory effect of morphine on the interaction in MIRI. In vivo and in vitro experiments were conducted. Coding RNA and pharmacological modulations were used in this study. We found MI/R (myocardial ischemia and reperfusion) upregulated p-TRPV1 without change in expression of NLRP3 inflammasome. Giving morphine during myocardial ischemia increased ventricular arrythmia, reduced heart rate and +dp/dt Max in reperfusion, and increased serum cTnI (cardiac troponin I) and infarct size. Suppression of p-TRPV1 but enhancement of NLRP3 inflammasome activity at the end of MI/R were detected. The alterations were reversed by an opioid μ-receptor antagonist or a NLRP3 inhibitor. Giving TRPV1 antagonist or knockdown of TRPV1 in cultured primary cardiomyocytes inhibited p-TRPV1 but increased NLRP3 inflammasome and the downstream cytokines and LDH (lactate dehydrogenase) in the supernatants. Conversely, treatment with capsaicin (a TRPV1 agonist) or upregulation of TRPV1 via transfection of Ad-TRPV1 elevated p-TRPV1 and reduced NLRP3 and LDH. The results indicated morphine treatment during myocardial ischemia aggravates MIRI by increasing the activity of NLRP3 inflammasome, via suppressing the inhibitory effect of p-TRPV1 on NLRP3 inflammasome. Targeting the signal chain of opioid μ-receptor agonist/TRPV1/NLRP3 inflammasome may find a novel way to improve MIRI.

The most common degenerative condition affecting the musculoskeletal system, and the leading cause of persistent low back pain, is intervertebral disc degeneration (IDD). IDD is increasingly common with age and has a variety of etiologic factors including inflammation, oxidative stress, extracellular matrix (ECM) degradation, and apoptosis that interact with each other to cause IDD. Because it is difficult to determine the exact pathogenesis of IDD, there is a lack of effective therapeutic agents. Melatonin has been intensively studied for its strong anti-inflammatory, antioxidant, and anti-apoptotic properties. Melatonin is a pleiotropic indole-stimulating hormone produced by the pineal gland, which can be used to treat a wide range of degenerative diseases. Therefore, melatonin supplementation may be a viable treatment for IDD. This article reviews the current mechanisms of IDD and the multiple roles regarding melatonin's anti-inflammatory, antioxidant, anti-apoptotic, and mitigating ECM degradation in IDD, incorporating new current research perspectives, as well as recent studies on drug delivery systems.

RING1 is an E3 ligase component of the polycomb repressive complex 1 (PRC1) with known roles in chromatin regulation and cellular processes such as apoptosis and autophagy. However, its involvement in inflammation and pyroptosis remains elusive. Here, we demonstrate that human RING1, not RING2, promotes K48-linked ubiquitination of Gasdermin D (GSDMD) and acts as a negative regulator of pyroptosis and bacterial infection. Indeed, we showed that loss of Ring1 increased S. typhimurium infectious load and mortality in vivo. Though RING1 deletion initially reduced M. tuberculosis (Mtb) infectious load in vivo, increased lung inflammation and impaired immune defense responses were later observed. Moreover, Ring1 knockout exacerbated acute sepsis induced by lipopolysaccharide (LPS) in vivo. Mechanistically, RING1 directly interacts with GSDMD and ubiquitinates the K51 and K168 sites of GSDMD for K48-linked proteasomal degradation, thereby inhibiting pyroptosis. Inhibition of RING1 E3 ligase activity by direct mutation or with the use of small molecule inhibitors increased GSDMD level and cell death during pyroptosis. Our findings reveal that RING1 dictates GSDMD-mediated inflammatory response and host susceptibility to pathogen infection, highlighting RING1 as a potential therapeutic target for combating infectious diseases.

Drug-induced toxicity is an important issue in clinical medicine, which typically results in organ dysfunction and adverse health consequences. The family of NOD-like receptors (NLRs) includes intracellular proteins involved in recognizing pathogens and triggering innate immune responses, including the activation of the NLRP3 inflammasome. The NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3) inflammasome is a critical component for both innate and adaptive immune responses and has been implicated in various drug-induced toxicities, including hepatic, renal, and cardiovascular diseases. The unusual activation of the NLRP3 inflammasome causes the release of pro-inflammatory cytokines, such as IL-1β and IL-18, which can lead to more damage to tissues. Targeting NLRP3 inflammasome is a potential therapeutic endeavour for suppressing drug-induced toxicity. This review provides insights into the mechanism, drug-induced organ toxicity, therapeutic strategies, and prospective therapeutic approaches of the NLRP3 inflammasome and summarizes the developing therapies that target the inflammasome unit. This review has taken up one of the foremost endeavours in understanding and inhibiting the NLRP3 inflammasome as a means of generating safer pharmacological therapies.

Spinal cord injury (SCI) is a severe disorder characterized by regeneration challenges in the central nervous system (CNS), resulting in permanent paralysis, loss of sensation, and abnormal autonomic functions. The complex pathophysiology of SCI poses challenges to traditional treatments, highlighting the urgent need for novel treatment approaches. Exosomes have emerged as promising candidates for SCI therapy because of their ability to deliver a wide range of bioactive molecules, such as RNAs, proteins, and lipids, to target cells with minimal immunogenicity, which contribute to anti-inflammatory, anti-apoptotic, autophagic, angiogenic, neurogenic, and axon remodeling activities. In this study, we classified exosomes from different sources into four categories based on the characteristics of the donor cells (mesenchymal stem cells, neurogenic cells, immune cells, vascular-associated cells) and provided a detailed summary and discussion of the current research progress and future directions for each source. We also conducted an in-depth investigation into the applications of engineered exosomes in SCI therapy, focusing on their roles in drug delivery and combination with surface engineering technologies and tissue engineering strategies. Finally, the challenges and prospects of exosomal clinical applications in SCI repair are described.

To investigate the anti-inflammatory effect of rutaecarpine (RUT) on monosodium urate crystal (MSU)-induced murine peritonitis in mice and further explored the underlying mechanism of RUT in lipopolysaccharide (LPS)/MSU-induced gout model in vitro.

In MSU-induced mice, 36 male C57BL/6 mice were randomly divided into 6 groups of 8 mice each group, including the control group, model group, RUT low-, medium-, and high-doses groups, and prednisone acetate group. The mice in each group were orally administered the corresponding drugs or vehicle once a day for 7 consecutive days. The gout inflammation model was established by intraperitoneal injection of MSU to evaluate the anti-gout inflammatory effects of RUT. Then the proinflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA) and the proportions of infiltrating neutrophils cytokines were detected by flow cytometry. In LPS/MSU-treated or untreated THP-1 macrophages, cell viability was observed by cell counting kit 8 and proinflammatory cytokines were measured by ELISA. The percentage of pyroptotic cells were detected by flow cytometry. Respectively, the mRNA and protein levels were measured by real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot, the nuclear translocation of nuclear factor κB (NF-κB) p65 was observed by laser confocal imaging. Additionally, surface plasmon resonance (SPR) and molecular docking were applied to validate the binding ability of RUT components to tumor necrosis factor α (TNF-α) targets.

RUT reduced the levels of infiltrating neutrophils and monocytes and decreased the levels of the proinflammatory cytokines interleukin 1β (IL-1β) and interleukin 6 (IL-6, all P<0.01). In vitro, RUT reduced the production of IL-1β, IL-6 and TNF-α. In addition, RT-PCR revealed the inhibitory effects of RUT on the mRNA levels of IL-1β, IL-6, cyclooxygenase-2 and TNF-α (P<0.05 or P<0.01). Mechanistically, RUT markedly reduced protein expressions of tumor necrosis factor receptor (TNFR), phospho-mitogen-activated protein kinase (p-MAPK), phospho-extracellular signal-regulated kinase, phospho-c-Jun N-terminal kinase, phospho-NF-κB, phospho-kinase α/β, NOD-like receptor thermal protein domain associated protein 3 (NLRPS), cleaved-cysteinyl aspartate specific proteinase-1 and cleaved-gasdermin D in macrophages (P<0.05 or P<0.01). Molecularly, SPR revealed that RUT bound to TNF-α with a calculated equilibrium dissociation constant of 31.7 µmol/L. Molecular docking further confirmed that RUT could interact directly with the TNF-α protein via hydrogen bonding, van der Waals interactions, and carbon-hydrogen bonding.

RUT alleviated MSU-induced peritonitis and inhibited the TNFR1-MAPK/NF-κB and NLRP3 inflammasome signaling pathway to attenuate gouty inflammation induced by LPS/MSU in THP-1 macrophages, suggesting that RUT could be a potential therapeutic candidate for gout.

The increasing global aging population has brought greater focus to age-related diseases, particularly muscle-brain comorbidities such as sarcopenia and late-life depression. Sarcopenia, defined by the gradual loss of muscle mass and function, is notably prevalent among older individuals, while late-life depression profoundly affects their mental health and overall well-being. Epidemiological evidence suggests a high co-occurrence of these two conditions, although the precise biological mechanisms linking them remain inadequately understood. This review synthesizes the existing body of literature on sarcopenia and late-life depression, examining their definitions, prevalence, clinical presentations, and available treatments. The goal is to clarify the potential connections between these comorbidities and offer a theoretical framework for the development of future preventive and therapeutic strategies.

Protein lipidation is a pivotal post-translational modification that increases protein hydrophobicity and influences their function, localization, and interaction network. Emerging evidence has shown significant roles of lipidation in the tumor microenvironment (TME). However, a comprehensive review of this topic is lacking. In this review, we present an integrated and in-depth literature review of protein lipidation in the context of the TME. Specifically, we focus on three major lipidation modifications: S-prenylation, S-palmitoylation, and N-myristoylation. We emphasize how these modifications affect oncogenic signaling pathways and the complex interplay between tumor cells and the surrounding stromal and immune cells. Furthermore, we explore the therapeutic potential of targeting lipidation mechanisms in cancer treatment and discuss prospects for developing novel anticancer strategies that disrupt lipidation-dependent signaling pathways. By bridging protein lipidation with the dynamics of the TME, our review provides novel insights into the complex relationship between them that drives tumor initiation and progression.