Inflammation-Responsive Drug Delivery System (IR-DDS) is proposed as a novel strategy for targeted therapy of the chronic inflammation-associated diseases: inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and sepsis. These smart systems take advantage of the characteristic pathological microenvironment in inflamed tissues-such as acidic pH (5-6.5), high levels of reactive oxygen species (ROS), overexpressed enzymes, including matrix metalloproteinases (MMPs), and reductive conditions from glutathione (GSH)-for drug-specific accumulation at the site of action and on-demand release. By capitalizing on stimulus-induced behaviors, such as pH-activated protonation and swelling, ROS-stimulated bond scission in thio-ketals or boronic esters, enzyme-cleavable peptide linkers, or GSH-triggered disulfides, IR-DDS have overcome drawbacks of traditional delivery systems, including low bioavailability, off-target effects, and systemic toxicity. The review discusses a variety of carrier systems, such as polymeric nanoparticles (PLGA, chitosan), liposomes, micelles, hydrogels, dendrimers, and hybrid nanocomposites that offer inherent biocompatibility, controllable degradation, and multiple functionalities for sustained delivery. This includes the use of muscle, pH-sensitive hydrogels for periodontitis, oxidation-responsive polypropylene sulfide nanoparticles for anti-inflammatory drug release in rheumatoid arthritis models, and enzyme-triggered gelatin complexes used to target inflamed tissue in IBD, which are striking examples. A sulfasalazine-loaded transdermal patch is shown for chronic inflammation assessment, with increased efficacy in preclinical animal models, such as rat colitis and mouse arthritis after localized delivery. Despite encouraging preclinical findings in lowering cytokine levels, joint swelling, and inflammation markers, clinical translation is hindered by disease heterogeneity, scalability, biocompatibility issues, and manufacturing complexity. Future perspectives: AI-guided green multi-stimuli systems and therapeutic drug delivery, and diagnostic imaging (such as fluorescence, MRI) using multifunctional nanoparticle hybrids for personalized precision therapy will most likely revolutionize the management of chronic inflammation.

KRAS mutations drive poor outcomes in colorectal cancer (CRC), largely by conferring resistance to radiotherapy. In clinical samples, we trace this resistance to an upregulated SLC7A11/GPX4 axis, a defense that shields cancer cells from ferroptosis. Targeting this pathway to re-enable ferroptosis, therefore, represents a rational strategy to restore radiosensitivity. Sulfasalazine (SAS), an FDA-approved drug, inhibits SLC7A11 and induces ferroptosis, but its clinical application is restricted by systemic toxicity and poor tumor accumulation. To bypass these limitations, we develop multifunctional SAS-loaded hafnium oxide nanoparticles (HfO2@SAS). Ultra-small HfO2@SAS enables efficient local drug retention and subsequent clearance, minimizing long-term retention risks and supporting favorable biocompatibility. HfO2@SAS serves a dual function: HfO2 amplifies radiotherapy via physical radiosensitization through X-ray energy deposition, while SAS disables antioxidant defenses to induce ferroptosis. In KRAS-mutant CRC, this nanoplatform overcomes radioresistance by integrating physical and biochemical mechanisms. Consistent with clinical sample data, we validate the efficacy of HfO2@SAS in cell and animal levels. Patient-derived organoids provide a human-relevant platform that further supports these findings. Collectively, these findings validate the potential of nanomedicine in combating refractory KRAS-mutant CRC and provide a proof-of-concept for advancing radio-drug combination therapy.

Rheumatoid arthritis is a chronic systemic autoimmune disease characterized by synovial inflammation, joint destruction, and systemic comorbidities. Emerging evidence highlights the critical involvement of the microbiome in disease pathogenesis, encompassing bacteria, viruses, fungi, and mycoplasmas. This review synthesizes recent findings on microbiome alterations, summarizing epidemiological, molecular, and mechanistic data. Among the evaluated pathogens, Porphyromonas gingivalis and Prevotella copri currently demonstrate the strongest causal evidence for initiating autoimmunity. Porphyromonas gingivalis directly catalyzes host protein citrullination via its unique peptidylarginine deiminase, driving anti-citrullinated protein antibody production, while Prevotella copri expands during the preclinical phase to drive T helper 17 cell polarization. Furthermore, chronic Hepatitis C virus infection presents compelling causal links, as continuous viral stimulation triggers robust autoantibody production in atypical memory B cells. Other infectious agents, including Epstein-Barr virus and Proteus mirabilis, act as environmental triggers through molecular mimicry, whereas opportunistic pathogens like Pneumocystis jirovecii emerge as severe secondary complications resulting from profound pharmacological immunosuppression. In terms of immediate clinical translation, several microbiome-targeted strategies are poised for routine practice. These include non-surgical periodontal therapy and oral hygiene optimization to reduce systemic disease activity, the utilization of direct-acting antivirals for Hepatitis C virus to concurrently resolve joint inflammation, and targeted prophylaxis using sulfasalazine to prevent Pneumocystis jirovecii pneumonia in highly immunosuppressed populations. Additionally, the immunomodulatory application of Ganoderma lucidum polysaccharides for symptomatic pain relief and the preclinical development of bacterial virulence factor inhibitors represent promising therapeutic avenues. Together, these findings confirm that the microbiome acts as a critical modifier of the inflammatory milieu. Future studies integrating longitudinal cohorts and precision interventional trials will further solidify causality and refine these microbiome-targeted therapies.

Poricoic acid A (PAA), a lanostane-type triterpenoid associated with Poria-derived medicines, has shown tissue-protective activity, but its effects on epithelial-barrier phenotypes and endpoint fecal microbiota in experimental colitis remain incompletely characterized. Male C57BL/6 mice were exposed to 3% dextran sulfate sodium (DSS) for 7 days and received oral PAA (2.5, 5, or 10 mg/kg/day), sulfasalazine (200 mg/kg/day), or vehicle concomitantly with DSS. Clinical disease indices and colon length were assessed; colonic histology, mucus-positive staining, epithelial ultrastructure, serum lipopolysaccharide (LPS), E-cadherin, and claudin-3 were evaluated; and endpoint fecal microbial communities were profiled by 16S rRNA gene sequencing. DSS caused body-weight loss, increased disease activity, colon shortening, histological injury, mucus depletion, epithelial ultrastructural disruption, increased serum LPS, and reduced colonic E-cadherin and claudin-3. PAA attenuated the clinical and histological changes, with the most consistent effects at 10 mg/kg/day, the highest dose tested. This group also showed better-preserved epithelial ultrastructure, lower serum LPS, and higher E-cadherin and claudin-3 signals than the DSS group. Endpoint sequencing showed higher richness-related indices in the PAA-H group than in the DSS group, including Chao1, ACE, observed species, and Faith's phylogenetic diversity, whereas Shannon and Simpson indices were not different. Exploratory taxonomic analyses identified treatment-associated differences in selected DSS-altered fecal taxa, including attenuation of Proteobacteria-related expansion. Thus, PAA administered during DSS exposure attenuated acute colitis and was accompanied by barrier-associated changes and endpoint fecal microbiota alterations.

Background/Objectives: Fibroblast-like synoviocytes (FLS) are key contributors to rheumatoid arthritis (RA) pathogenesis, driving synovial inflammation, cartilage degradation, bone erosion and disease persistence. Recent advances have revealed substantial FLS heterogeneity, with distinct fibroblast subsets exhibiting different pathogenic roles within the rheumatoid synovium. Although disease-modifying antirheumatic drugs (DMARDs) constitute the cornerstone of RA treatment, their effects on FLS have not been comprehensively characterised. This review summarises and compares the effects of conventional synthetic DMARDs (csDMARDs), biologic DMARDs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) on RA-FLS. Methods: A non-systematic literature review was conducted to identify studies investigating the effects of DMARDs on RA-FLS. Studies evaluating the impact of csDMARDs, bDMARDs and tsDMARDs on FLS proliferation, apoptosis, migration, invasion, inflammatory mediator production, extracellular matrix remodelling and osteoclastogenic activity were included. Results: Available evidence indicates that DMARDs modulate multiple pathogenic functions of RA-FLS. Methotrexate, leflunomide, hydroxychloroquine and sulfasalazine regulate inflammatory signalling, apoptosis, autophagy and ferroptosis. Biologic agents, particularly tumour necrosis factor alpha (TNF-α) and interleukin (IL)-6 receptor inhibitors, suppress cytokine production, matrix metalloproteinase expression, osteoclastogenic signalling and FLS migration. Targeted synthetic DMARDs, particularly Janus kinase inhibitors (JAKis), exhibit broad activity across inflammatory, angiogenic, metabolic and tissue-destructive pathways. Despite their distinct molecular targets, all DMARD classes ultimately attenuate key pathogenic FLS functions associated with synovial inflammation and joint destruction. Conclusions: JAKis exert broad effects on RA-FLS function in vitro, likely reflecting their ability to block multiple cytokine-dependent signalling pathways. However, clinical evidence linking these effects to patient outcomes remains limited; further validation is therefore required.

Anthracycline cardiotoxicity involves early oxidative-inflammatory injury to the myocardium and vasculature. Repurposing anti-inflammatory agents may offer pragmatic cardioprotection. The purpose of this study is to evaluate whether sulfasalazine (SSZ) mitigates doxorubicin (DOX)-induced myocardial and aortic injury in rats. Twenty-eight male Wistar albino rats were randomized to: Control (vehicle, n = 8), DOX (20 mg/kg i.p., single dose; n = 10), and SSZ + DOX (SSZ 300 mg/kg i.p. once daily for 3 days, then DOX 20 mg/kg i.p.; n = 10). At 24 h post-DOX, ECG and invasive blood pressure (BP) were recorded. The heart and thoracic aorta were harvested for histopathology and oxidative stress assays (MDA, SOD, GSH, CAT; composite indices where applicable). Compared with SSZ + DOX, the DOX group exhibited higher BP and greater arrhythmic burden. In the aorta, DOX elevated MDA and reduced SOD, GSH, and CAT versus the control, whereas SSZ + DOX shifted these toward control values. In the myocardium, DOX decreased SOD and increased oxidative index; SSZ + DOX attenuated histological injury (edema, hemorrhage, cardiomyocyte degeneration) and restored aortic intima-media thickness toward control. Heart rate was lower in SSZ + DOX than other groups. Short-course SSZ pretreatment alleviated early DOX-induced oxidative stress and structural damage in myocardial and aortic tissues, with concurrent improvement in hemodynamic and ECG profiles. These data support further dose-timing optimization and longer-term functional studies to define SSZ's translational potential as an adjunct cardioprotective strategy during anthracycline exposure.

New mixed ligand compounds FeSUPT and CoSUPT were successfully prepared using sulfasalazine (SU) and phenanthroline (PT). The compounds were recovered as solid, non-electrolyte substances with good thermal stability (above 300°C) and low molar conductivities (11.85 and 10.63 Ω[-1]cm[2]mol[-1]). Elemental and spectroscopic analyses confirmed the proposed formulations and a 1:1:1 metal-to-ligand ratio. FT-IR data indicated coordination through phenolic oxygen, and carboxylate oxygen from SU, and nitrogen atoms from PT. Electronic spectra and magnetic moments (1.85 and 1.80 B.M.) supported octahedral geometries. TGA results confirmed coordinated water molecules and high structural stability. DFT calculations revealed reduced energy gaps for FeSUPT (2.27 eV)and CoSUPT (2.11 eV), indicating higher reactivity compared to SU (3.37 eV) and PT (4.65 eV). The complexes also showed higher softness (0.44-0.47) and electrophilicity (up to 8.98 eV). Biological evaluation showed a strong enhancement after complexation. Antibacterial activity reached 24-27 mm for the complexes, compared to 5-8 mm for ligands. Activity indices approached 96%, close to amoxicillin. Antifungal activity displayed inhibition zones up to 18 mm, with activity indications reaching 90%. MIC values decreased significantly to 40-50 μM for the complexes, compared to 90-100 μM for ligands. Molecular docking studies against DNA gyrase B (PDB ID: 1KZN) revealed favorable binding affinities, particularly for CoSUPT (-8.40 kcal/mol). These results provide preliminary computational support for the observed antibacterial activity, although they do not constitute direct evidence of enzyme inhibition.

Acne vulgaris, driven by Propionibacterium acnes infection, is poorly addressed by conventional phototherapy due to oxygen dependence, transient efficacy, and pro-inflammatory side effects. Herein, we design a ternary coordination polymer (Fe-SASP/ART) that overcomes these limitations while promoting keratinocyte proliferation. The first formed Fe-sulfasalazine (SASP) precursors exhibit photothermal and photodynamic properties via ligand-to-metal charge transfer (LMCT). Artemisinin (ART) serves as coordinating ligands and structural inducers, transforming amorphous precursors into crystalline frameworks. The ART-directed architecture enables oxygen-independent carbon-centered radical generation via Fe[2] [+]-catalyzed ART cleavage (Fe[2+] generated from LMCT), establishing a dual-channel energy dissipation pathway that enhances photothermal and photodynamic performance. Notably, the iron-mediated activation of ART establishes a self-sustaining Fe[3+]/Fe[2+] redox cycle, driving prolonged radical production post-irradiation for sustained antibacterial effect. The nanoplatform achieves 69.5% bactericidal efficacy against P. acnes upon NIR irradiation, suppresses pro-inflammatory cytokines via SASP, and promotes keratinocyte proliferation (120.9% viability) through hormesis. Ex vivo studies confirm efficient follicular accumulation of the nanoplatform with controlled penetration depth. In mouse acne models, a single topical treatment with NIR irradiation elicits sustained lesion resolution over 5 days, with potent therapeutic efficacy, anti-inflammatory effects, and excellent biocompatibility. This work offers a promising paradigm for safe and effective acne management.

SUMOylation is characterized as a ubiquitin-like post-translational modification that exhibits mechanistic similarities with ubiquitination. Importantly, it modulates the ubiquitination levels of some target proteins, thereby influencing protein stability. Dysregulation of this modification pathway plays a pivotal role in the pathogenesis and progression of various tumors. While recent studies have demonstrated that protein SUMOylation regulates tumor progression, the specific function and mechanism of Ran-binding protein 2 (RanBP2), an E3 SUMO ligase, remain to be elucidated in lung adenocarcinoma (LUAD). This study demonstrates that RanBP2 exhibits elevated expression in LUAD and correlates with poor prognosis. Functionally, RanBP2 inhibits ferroptosis and enhances the growth of LUAD cells. Mechanistically, RanBP2 augments the SUMOylation of E3 ubiquitin ligase leucine-rich repeat and sterile alpha motif-containing protein 1 (LRSAM1), facilitating its subsequent degradation in the ubiquitin-proteasome pathway, thereby reducing SLC7A11 degradation. The stabilized SLC7A11 protein suppresses ferroptosis and promotes LUAD cell growth. The identified RanBP2 inhibitor, amodiaquine (AQ), in combination with ferroptosis inducer sulfasalazine (SAS), effectively triggered ferroptosis and suppressed LUAD cell growth in vitro and in vivo. This combination enhanced T-cell infiltration and improved anti-PD-1 immunotherapy efficacy. The research identifies a novel RanBP2-LRSAM1-SLC7A11 axis that promotes ferroptosis resistance and LUAD progression. The combination of AQ and SAS represents a promising therapeutic strategy for LUAD.

Primary hypertrophic osteoarthropathy (PHO) is a rare genetic disorder that closely mimics inflammatory arthritis, leading to diagnostic delays and inappropriate treatment. We report the case of an adolescent boy who presented with a 2-year history of intermittent joint pain and swelling and was initially diagnosed with juvenile idiopathic arthritis at a primary care centre. He was treated with sulfasalazine but experienced only partial symptomatic relief. Laboratory evaluation at the referring centre showed a negative rheumatoid factor and mildly elevated C-reactive protein. Persistent symptoms prompted re-evaluation, which revealed clinical features and a positive family history consistent with PHO. Recognition of characteristic clinical findings and family history led to the correct diagnosis, allowing discontinuation of the disease-modifying anti-rheumatic therapy. This case highlights the importance of considering PHO in the differential diagnosis of chronic arthritis in children, particularly in those with a positive family history.

Livedoid vasculopathy (LV) is a rare thrombo-occlusive disorder of the dermal microcirculation that may clinically resemble inflammatory vasculitis. In patients with rheumatoid arthritis (RA), the development of painful lower extremity ulcers often raises concern for rheumatoid vasculitis, making histopathological evaluation essential for accurate diagnosis and treatment selection. We present a case of a 45-year-old man with an eight-year history of seropositive RA receiving methotrexate, sulfasalazine, and baricitinib who developed painful lower extremity ulcers, edema, and episcleritis in the setting of high disease activity (Disease Activity Score 28 using C-reactive protein {DAS28-CRP} of 6.23). Given the suspicion of rheumatoid vasculitis, an extensive diagnostic workup was performed. Laboratory studies demonstrated elevated inflammatory markers and negative antineutrophil cytoplasmic antibodies. Skin biopsy revealed vascular wall hyalinization, luminal obliteration, and fibrin thrombi in the absence of inflammatory infiltrates or fibrinoid necrosis, establishing the diagnosis of livedoid vasculopathy. Treatment with systemic glucocorticoids and rituximab, administered according to the standard rheumatoid arthritis regimen, resulted in partial improvement in ocular inflammation, joint symptoms, and cutaneous ulceration. Anticoagulant therapy was not initiated because treatment escalation was primarily directed toward uncontrolled rheumatoid arthritis and severe extra-articular manifestations. Histopathological examination demonstrated vascular wall hyalinization, luminal obliteration, and fibrin thrombi in the absence of significant vascular inflammation or fibrinoid necrosis, establishing the diagnosis of livedoid vasculopathy and excluding rheumatoid vasculitis. Although initial clinical improvement was observed, recurrent ocular symptoms and persistent lower extremity ulceration developed following interruption of biologic therapy. Histopathological confirmation demonstrating thrombotic microvascular occlusion without vascular inflammation was essential for establishing the diagnosis and avoiding misclassification as rheumatoid vasculitis. This case highlights the importance of tissue diagnosis in patients with RA presenting with ulcerative cutaneous lesions and emphasizes the need to consider livedoid vasculopathy in the differential diagnosis of suspected rheumatoid vasculitis.