bims-supasi 2026-10-04 papers

bims-supasi

Biomed News

on Sulfation pathways and signalling

Issue of 2026–10–04
thirteen papers selected by
Jonathan Wolf Mueller, University of Birmingham

Marine sulfated glycans inhibit the binding of Borrelia burgdorferi adhesins to heparin/GAGs.
Heparan sulfate sulfation modification in airway mucosal barrier: biosynthetic regulation, pathological implications, and therapeutic targets in allergic respiratory diseases.
Indoxyl sulfate in the gut-kidney axis: from diet-microbiome interactions to renal injury and targeted therapies.
Chondroitin sulfate shapes the unfolded protein response in osteosarcoma to sustain cancer cell survival during ER stress.
Bombyx mori-Hosted Cordyceps militaris Polysaccharides: Structural Characterization and Antibacterial Activity of Native and Sulfated Derivatives.
Heparan sulfate endosulfatases, Sulf1 and Sulf2, are required for formation of the medial habenula-interpeduncular nucleus circuit.
An RBP-J-heparan sulfate-dependent gatekeeper directs macrophage fate between inflammatory regulation and osteoclastogenesis.
Protein tyrosine sulfation: from molecular mechanisms and pathophysiology to analytical advances and therapeutic translation.
Nutritional coordination via sulfate transport drives Beauveria bassiana-plant endophytism.
Atomic resolution structure of human papillomavirus bound to heparin.
The Sulfated PSY Peptide Negatively Regulates Receptor Kinase Activity to Promote Growth.
Signaling by a tyrosine-sulfated peptide balances growth and osmotic stress response in rice.
Association of baseline peripheral sex hormone profiles and metabolic parameters with recurrence after oral isotretinoin treatment in patients with severe acne.

bioRxiv. 2026 Sep 23. pii: 2026.09.22.753655. [Epub ahead of print]

Marine sulfated glycans inhibit the binding of Borrelia burgdorferi adhesins to heparin/GAGs.

Changkai Bu, Ke Xia, Carly Fernandes, Yi-Pin Lin, Nikhat Parveen, Vitor H Pomin, Jonathan S Dordick, Lianli Chi, Fuming Zhang.

Recognition of host glycosaminoglycans (GAGs) is critical for the adhesion and colonization of Borrelia burgdorferi , but the structural requirements for these interactions remain incompletely understood. Using surface plasmon resonance (SPR), we characterized the heparin-binding properties of three Borrelia adhesins, i.e. Bgp, DbpA-A9, and DbpB-B31 and evaluated inhibitors comprising heparin oligosaccharides, selectively desulfated heparins, mammalian GAGs, marine sulfated glycans, pentosan polysulfate (PPS), and mucopolysaccharide polysulfate (MPS). All three adhesins bound directly to heparin, with equilibrium dissociation constants ( K D ) of 2.18 nM for Bgp and 36.4 nM for DbpB-B31. Competition assays identified N- sulfation and 6- O -sulfation as major determinants of binding, whereas 2- O -sulfation had a lower effect. Bgp showed chain-length dependence over dp4-dp20, whereas DbpB-B31 preferentially recognized longer oligosaccharides, particularly those of dp12 or greater. Chondroitin sulfate E also exhibited strong inhibitory activity, indicating that recognition was not restricted to heparin/heparan sulfate backbones. Among the tested sulfated glycans, fucosylated chondroitin sulfate (HfFucCS) from Holothuria floridana was the most potent inhibitor of Bgp, with an IC 50 of approximately 4 ng/mL, whereas PPS was the strongest inhibitor of DbpB-B31, followed by MPS. These findings reveal protein-specific sulfated-glycan recognition and identify promising candidates for disrupting B. burgdorferi -host GAG interactions.

DOI: https://doi.org/10.64898/2026.09.22.753655
Int Immunopharmacol. 2026 Sep 27. pii: S1567-5769(26)01314-7. [Epub ahead of print]190 117467

Heparan sulfate sulfation modification in airway mucosal barrier: biosynthetic regulation, pathological implications, and therapeutic targets in allergic respiratory diseases.

Chenghong Sun, Ting Yang.

  Heparan sulfate (HS) is a highly sulfated glycosaminoglycan essential for airway mucosal barrier function. Its biological activities are determined by the "sulfation code" generated through N-deacetylase/N-sulfotransferases (NDST1-4) and O-sulfotransferases. Emerging evidence indicates that HS sulfation operates within a narrow homeostatic range - a "rheostat" - where both insufficient and excessive sulfation disrupt barrier integrity and promote inflammation. This review proposes the HS sulfation rheostat model as a unifying framework for allergic respiratory diseases. We examine the HS biosynthetic machinery and its regulation at transcriptional, epigenetic, and metabolic levels, with emphasis on histone lactylation as a metabolic-epigenetic rheostat for HS enzyme expression. We summarize HS functions within the homeostatic range, including glycocalyx integrity, tight junction regulation, and growth factor signaling. We then discuss rheostat dysregulation in allergic airway inflammation, focusing on evidence from NDST1-deficient mice demonstrating that HS N-sulfation mediates eosinophil recruitment, chemokine sequestration, and airway remodelling. Key controversies are appraised, including the NDST1 versus NDST3 debate, cell-type-specific functions, and the translational gap. Finally, we highlight therapeutic strategies for restoring the rheostat, including non-anticoagulant heparin derivatives, defined HS oligosaccharides, heparanase inhibitors, and HS glycomimetics. Understanding the HS sulfation rheostat and its regulation through the glycoepigenetics axis may identify new therapeutic targets for allergic rhinitis, asthma, and related airway diseases. Compartment-specific set points are emphasized throughout: epithelial sulfation reinforces barrier integrity, whereas endothelial and leukocyte sulfation governs leukocyte recruitment and chemokine presentation.

Keywords:  Airway mucosal barrier; Allergic airway inflammation; Heparan sulfate; N-deacetylase/N-sulfotransferases; Sulfation rheostat

DOI:  https://doi.org/10.1016/j.intimp.2026.117467
Front Nutr. 2026 ;13 1881019

Indoxyl sulfate in the gut-kidney axis: from diet-microbiome interactions to renal injury and targeted therapies.

Xiangning Huang, Xinyu Yang, Jiawang Huang, Wang Tao, Yunfeng Yu, Rong Yu.

  Indoxyl sulfate (IS) is a prototypical protein-bound uremic toxin, linking dietary tryptophan metabolism by gut microbiota to renal injury. Derived from dietary tryptophan metabolized by gut microbiota into indole, which is subsequently transported to the liver and sulfated to form IS. In circulation, IS binds serum albumin and is actively secreted into urine via renal tubular organic anion transporters. In chronic kidney disease (CKD), impaired renal clearance and altered albumin-binding capacity contribute to IS accumulation and an increased free fraction. IS exerts nephrotoxic effects through multiple mechanisms. As an endogenous ligand of the aryl hydrocarbon receptor (AHR), it activates AHR signaling and contributes to mitochondrial dysfunction, oxidative stress, inflammation, regulated cell death, and renal fibrosis through interconnected downstream pathways. Therapeutic strategies targeting IS include dietary and microbiota-based interventions, oral adsorbent AST-120, modified dialysis approaches, and traditional Chinese medicine interventions. Although these strategies may reduce IS exposure or its downstream effects, the current evidence is predominantly derived from preclinical studies and surrogate-endpoint assessment. Further well-designed clinical trials are needed to determine whether reducing IS exposure can translate into sustained improvements in renal and patient-centered outcomes.

Keywords:  chronic kidney disease; indoxyl sulfate; mechanisms of renal injury; protein-bound uremic toxin; targeted therapy

DOI:  https://doi.org/10.3389/fnut.2026.1881019
Cell Death Dis. 2026 Aug 01. pii: 840. [Epub ahead of print]17(1):

Chondroitin sulfate shapes the unfolded protein response in osteosarcoma to sustain cancer cell survival during ER stress.

Maj Sofie Ørum-Madsen, Jessica Pihl, Thomas M Clausen, Charlotte Spliid, Anne-Chloé Dhez, Hai-Feng Zhang, Yen-Hsi Chen, Elena Ethel Vidal-Calvo, Tobias Gustavsson, Michael Lizardo, Irina Nelepcu, Joey Lo, Jeffrey D Esko, Htoo Zarni Oo, Alberto Delaidelli, Mette Ørskov Agerbæk, Anne Steinø, Nader Al Nakouzi, Ali Salanti, Poul Sorensen, Mads Daugaard.

Tumors must adapt to high levels of endoplasmic reticulum (ER) stress to sustain tumor growth and metastases. The chaperone GRP78 (BiP/HSPA5) is a key component of the unfolded protein response (UPR) and essential for ER stress management and adaptive signaling supporting pro-survival UPR activities. Here, we report that oncofetal chondroitin sulfate (CS) glycosaminoglycans are required for ER stress adaptation in osteosarcoma. When osteosarcoma cells encounter ER stress, they upregulate 4-O-sulfated CS at the expense of other glycosaminoglycans leading to a reconfiguration of the glycocalyx in favor of an oncofetal CS subtype. Genetic ablation of the CS synthesis pathway impairs the UPR by preventing osteosarcoma cells from mounting GRP78 expression in response to ER stress. CS deficiency makes osteosarcoma cells hypersensitive to inhibition of GRP78 under both ambient and ER stress conditions, and acute ER stress drives CS-defective osteosarcoma cells into an apoptotic cell death that can be rescued by re-instating CS 4-O-sulfation capacity. This has direct implications for the metastatic progression of osteosarcoma, whereby oncofetal CS protects dissociated osteosarcoma cells from anoikis to allow pulmonary colonization in mice. Our data identify CS glycosaminoglycans as a critical component of the UPR that permits osteosarcoma cells to manage ER stress.

DOI: https://doi.org/10.1038/s41419-026-09151-9
Chem Biodivers. 2026 Oct;23(10): e71798

Bombyx mori-Hosted Cordyceps militaris Polysaccharides: Structural Characterization and Antibacterial Activity of Native and Sulfated Derivatives.

Jingchun Yang, Jiani Cheng, Gaoyang Li, Wenpu Shi, Yaqi Liu, Tingyu Luo, Lixue Zheng.

  Polysaccharides from Bombyx mori-hosted Cordyceps militaris are abundant but exhibit limited bioactivity, necessitating exploration of sulfated derivatives. In this study, crude polysaccharides (Bm-CMP) were extracted and further sulfated to obtain four derivatives (Bm-sCMP-1∼4). Physicochemical and structural analyses indicated that sulfation significantly modified the characteristics of Bm-CMP, notably reducing the molecular weight (Mw) and particle size while enhancing the negative surface charge and altering the monosaccharide profile. All sulfated derivatives exerted enhanced inhibitory effects against Escherichia coli and Bacillus subtilis, which were closely dependent on the degree of substitution (DS), sulfate content, and negative charge density. Notably, Bm-sCMP-2, with a moderate DS, displayed the optimal antibacterial efficacy. Collectively, this work demonstrates that sulfation is a feasible strategy to valorize polysaccharides from B. mori-hosted C. militaris, transforming them into promising candidates for novel antibacterial agents, although their in vivo efficacy and safety require further validation.

Keywords:  Bombyx mori‐hosted Cordyceps militaris; antibacterial activity; polysaccharides; structural characterization; sulfated modification

DOI:  https://doi.org/10.1002/cbdv.71798
Front Neuroanat. 2026 ;20 1961110

Heparan sulfate endosulfatases, Sulf1 and Sulf2, are required for formation of the medial habenula-interpeduncular nucleus circuit.

Sayaka Hashimoto, Takuya Okada, Kazuko Keino-Masu, Ken Miya, Masayuki Masu.

  The medial habenula (MHb), a medial subdivision of the habenula located in the dorsal diencephalon, sends axons towards the interpeduncular nucleus (IPN) through the fasciculus retroflexus. Upon reaching the IPN, MHb axons cross the midline multiple times. Although heparan sulfate proteoglycans have previously been shown to play a role in MHb axon guidance, the role of heparan sulfate 6-O-endosulfatases, Sulfatase 1 (Sulf1) and Sulfatase 2 (Sulf2), has to date not been investigated. We thus examined MHb axon trajectories in Sulf1 and Sulf2 knockout mice and found that Sulf1/2 double knockout (DKO) mice showed several types of pathfinding errors after reaching the ventral surface of the brain. The abnormalities included aberrant anterior extension into the mammillary body, abnormal lateral projection on the brain surface, and reduced midline crossing within the IPN. Furthermore, the DKO mice exhibited altered outcomes in social conflict in a tube test assay: they showed a higher win rate against wild-type mice. This behavioral phenotype may reflect functional impairment of the MHb-IPN circuit resulting from its developmental abnormalities. Taken together, these findings suggest that Sulf1/2 are required for proper MHb-IPN circuit formation during development, which is in turn critical for its normal function in adulthood.

Keywords:  Sulfatase 1; Sulfatase 2; axon guidance; habenula; interpeduncular nucleus; midline crossing

DOI:  https://doi.org/10.3389/fnana.2026.1961110
bioRxiv. 2026 Sep 07. pii: 2026.09.02.749003. [Epub ahead of print]

An RBP-J-heparan sulfate-dependent gatekeeper directs macrophage fate between inflammatory regulation and osteoclastogenesis.

Ting Zheng, Huanmeng Hao, Jialin Jiang, Zhangjie Wang, Miaomiao Li, Courtney Ng, Jian Liu, Ding Xu, Baohong Zhao.

Macrophages in bone possess a unique bi-potential capacity. Different from their primary roles in inflammation and immunity, these cells can differentiate into bone-resorbing osteoclasts. However, it remains unclear how macrophages determine which function to engage in bone, especially when exposed to the same stimulus, such as TNF, which can drive both pathways. Understanding these mechanisms is particularly important in inflammatory bone diseases, such as rheumatoid arthritis, where inflammation and bone resorption are hallmarks. Here, we identified an RBP-J-Hs2st1-2-O-sulfated heparan sulfate (HS)-IFNβ dependent molecular network that acts as a gatekeeper balancing macrophage fate inclinations in response to TNF. This network integrates cellular outside-in, inside-out, and relayed outside-in pathways. RBP-J deficiency in macrophages shifts TNF action from inflammatory regulation to osteoclastogenesis. Hs2st1, the exclusive biosynthetic enzyme for 2-O sulfation of HS, is a key target suppressed by RBP-J. Loss of Hs2st1 significantly reduces inflammatory osteoclastogenesis and arthritic bone erosion without affecting physiological bone mass. Elevated Hs2st1 expression and 2-O sulfation shift macrophages toward an osteoclastogenic fate, and vice versa. We further identified residues in IFNβ that are responsible for binding HS. Mutation of these sites diminished HS binding, augmented type I IFN response, and more strongly suppressed osteoclastogenesis. Our findings reveal a previously unrecognized molecular program fine-tuning macrophage fate and function, and highlight potential therapeutic strategies for inflammatory diseases with bone defects.

DOI: https://doi.org/10.64898/2026.09.02.749003
Biochem Pharmacol. 2026 Sep 30. pii: S0006-2952(26)00854-3. [Epub ahead of print]254(Pt 3): 118512

Protein tyrosine sulfation: from molecular mechanisms and pathophysiology to analytical advances and therapeutic translation.

Wenqing Liu, Qingqing Zou, Wenyi Liu, Zhen Huang.

  Protein tyrosine sulfation (PTS), catalyzed by the Golgi-resident tyrosylprotein sulfotransferases 1 and 2 (TPST1 and TPST2) using 3'-phosphoadenosine 5'-phosphosulfate (PAPS) as the sulfuryl donor, regulates extracellular protein-protein interactions but remains analytically challenging because sulfotyrosine is labile and nearly isobaric with phosphotyrosine. This review summarizes the molecular and structural basis of TPST-mediated sulfation, its roles in infection, cancer, immunity, and cardiovascular disease, and recent advances in sulfoproteomics, including open-search mass spectrometry and single-molecule nanopore sensing. We critically evaluate non-canonical cytoplasmic and nuclear sulfation claims and emphasize the need for topology-aware, orthogonal validation. We also propose the PAPS pool hypothesis as a testable framework for examining how PAPS synthesis, Golgi transport, and pathway-specific consumption may shape protein and glycan sulfation, together with a four-step validation framework for non-canonical assignments and a compartmentalized kinase-crosstalk model for selected topological discrepancies. Finally, we assess emerging therapeutic strategies and their key limitations, including selectivity, Golgi access, pharmacokinetics, toxicity, and effects on other PAPS-dependent pathways. Overall, this review provides an evidence-based framework for defining the boundaries of PTS and guiding future analytical and therapeutic studies.

Keywords:  Isobaric misannotation; PAPS pool hypothesis; Precision therapeutics; Protein tyrosine sulfation; Sulfoproteomics; Tyrosylprotein sulfotransferase

DOI:  https://doi.org/10.1016/j.bcp.2026.118512
Plant Physiol. 2026 Sep 28. pii: kiag723. [Epub ahead of print]

Nutritional coordination via sulfate transport drives Beauveria bassiana-plant endophytism.

Yunxia Liu, Yutong Long, Yazhuo Li, Xin Zhao, Fanlong Wang, Zhibing Luo, Yongjun Zhang.

  The entomopathogenic fungus Beauveria bassiana endophytically colonizes a diverse array of plants including the model, Nicotiana benthamiana stimulating photosynthesis and growth. During this interaction, sulfate transporter genes are upregulated in both organisms. However, the mechanisms mediating this potential mutualistic sulfate exchange remain elusive. Here, we demonstrate that the three activated fungal sulfate transporters synergistically facilitated sulfate utilization and promoted fungal colonization of the plant. Among these, the high-affinity sulfate transporter BbSulTR1 plays a primary role. Disruption of any single fungal sulfate transporter genes decreased B. bassiana plant colonization, consequently decreasing plant sulfur accumulation and growth promotion. Similarly, single interference of the three activated plant sulfate transporter genes severely attenuated plant sulfate acquisition and biomass, subsequently restricting fungal colonization. Mechanistically, the endophytic fungus actively acquires sulfate from the host to enhance its own organic sulfur synthesis. This depletion of host sulfate and organic sulfur pools triggers the plant's low-sulfur response, upregulating host sulfate transporters to accelerate external sulfate uptake. Notably, loss of BbSulTR1 significantly abolished these reciprocal dynamics. Our findings reveal that fungal sulfate acquisition is critical for fungal endophytic colonization, and that the mutualistic interaction integrates a feedback mechanism which stimulates host sulfur assimilation pathways ultimately contributing to plant growth. This study elucidates a novel nutritional coordination mechanism underpinning fungal plant endophytism.

Keywords:  entomopathogenic fungi; fungal colonization of plant; plant growth promotion; sulfate acquisition; sulfate transporter

DOI:  https://doi.org/10.1093/plphys/kiag723
Nat Commun. 2026 Aug 26. pii: 10239. [Epub ahead of print]17(1):

Atomic resolution structure of human papillomavirus bound to heparin.

Caroline H Langley, Daniel J Goetschius, Santiago Antolínez, Ebere Precious Orji, Carol M Bator, Sarah A Brendle, Neil D Christensen, Jodi A Hadden-Perilla, Susan L Hafenstein.

Human papillomavirus (HPV) is a significant health burden and leading cause of virus-induced cancers. The mechanisms of HPV receptor binding and host entry are not completely understood, although it is known that heparan sulfate proteoglycans (HSPGs) mediate entry. HPV16 quasivirus, composed of L1 and L2 capsid proteins with a packaged cottontail rabbit papillomavirus genome was incubated with heparin. The complex was vitrified, and data were collected for cryoEM single particle analysis. Subparticles were extracted and hexavalent and pentavalent capsomers were refined separately. Here we present the resulting 1.9 Å resolution structure, with heparin visualized around the capsomer at the icosahedral fivefold vertex. A model of the asymmetric unit was built unambiguously into the atomic resolution cryoEM map. Hydrogen bonds are predicted between L1 N-terminal regions, which are supported by molecular dynamics. The heparin binding site was identified, along with local L1 conformational changes and global flexibility changes. These changes induced by heparin binding likely reflect the structure of HPV during early stages of entry and provide a framework for future HPV biochemical, genetic, and biophysical studies.

DOI: https://doi.org/10.1038/s41467-026-77019-9
bioRxiv. 2026 Sep 02. pii: 2026.07.25.740709. [Epub ahead of print]

The Sulfated PSY Peptide Negatively Regulates Receptor Kinase Activity to Promote Growth.

Devin V Tulio, Alexandra M Shigenaga, Dawn Lim, Artur Teixeira de Araujo, Shu-Zon Wu, Pamela C Ronald, Magdalena Bezanilla.

Complex signaling pathways organize cell expansion and proliferation across cells to pattern tissues and organs in plants. The sulfotyrosine peptide hormone family, PLANT PEPTIDE CONTAINING SULFATED TYROSINE (PSY), contributes to these processes. We identified two plasma membrane-localized receptors, PSYR1 and PSYR2, that are necessary for PSY signaling and regulate growth in Physcomitrium patens. Membrane-associated PSYRs accumulate to high levels in a mutant lacking TYROSYL PROTEIN SULFOTRANSFERASE (TPST). Given that a tpst null mutant (Δtpst) is impaired in sulfation, this suggests that in the absence of sulfated peptides, PSYRs accumulate on the membrane. A null mutant of the PSY receptors, Δpsyr1/2, showed increased growth and was epistatic to Δtpst, suppressing defects in gametophore formation and early senescence. The transcriptional profiles comparing wild type to Δpsyr1/2 and Δpsyr1/2/Δtpst showed 25 to 30 differentially expressed genes between the receptor null mutants and wild type, with a common signature of cell wall remodeling and stress responses. Similarly, a PSYR1 kinase-inactive mutation rescued Δtpst and relieved the accumulation of membrane-associated PSYRs. In contrast, overexpression of PSYRs inhibited plant growth, with phenotypic severity correlating with the amount of overexpression. These data are consistent with a constitutive activation model in which membrane-associated PSYRs unbound to PSY serve to inhibit growth through an active kinase. In the presence of the PSY peptide, the kinase is inactivated, promoting growth and driving PSY expression. The relationship between growth-repressive PSYR kinase activity and growth-promoting PSYR kinase inactivation in P. patens serves as a model for optimizing plant growth and development.

DOI: https://doi.org/10.64898/2026.07.25.740709
Proc Natl Acad Sci U S A. 2026 Oct 06. 123(40): e2622107123

Signaling by a tyrosine-sulfated peptide balances growth and osmotic stress response in rice.

Yejin Shim, Ellen Y Rim, Jin C-Y Liao, Myeong-Je Cho, George Austin, Patrick W Carlos, Sameer S Kulkarni, Richard J Payne, Maria Florencia Ercoli, Pamela C Ronald.

  Peptide hormone signaling coordinates plant growth and osmotic stress responses, yet how the transition between these responses is regulated remains poorly understood. Here, we investigated the function of the rice PLANT PEPTIDES CONTAINING SULFATED TYROSINE 8 (OsPSY8) peptide in osmotic stress responses. OsPSY8 was predominantly expressed in root tissues under nonstress conditions, with preferential expression in lateral roots where it promoted root growth. Osmotic stress rapidly reduced OsPSY8 expression in roots through the OsWRKY24 transcription factor. Loss-of-function ospsy8 mutants exhibited enhanced osmotic stress tolerance, whereas OsPSY8 overexpression increased osmotic stress susceptibility. Transcriptomic analyses revealed that disruption of OsPSY8 activated stress-responsive pathways, including those associated with lignin biosynthesis, compatible solute production, cell wall remodeling, and reactive oxygen species scavenging, and was accompanied by increased lignin accumulation in roots. In contrast, overexpression of OsPSY8 resulted in maintenance of growth-associated transcriptional programs while suppressing stress-responsive pathways under osmotic stress. Together, these findings identify OsPSY8 as an important regulator of the transition from growth to stress adaptation in rice and suggest that stress-induced repression of PSY signaling is required to disengage growth programs and activate adaptive responses during osmotic stress.

Keywords:  osmotic stress; rice; tyrosine-sulfated peptide

DOI:  https://doi.org/10.1073/pnas.2622107123
Front Endocrinol (Lausanne). 2026 ;17 1912708

Association of baseline peripheral sex hormone profiles and metabolic parameters with recurrence after oral isotretinoin treatment in patients with severe acne.

Li-Fen Song, Yang Xiao, Hui Zhang.

   Background: Acne recurrence after oral isotretinoin remains common, but the clinical, treatment-related, hormonal, and metabolic factors associated with recurrence are not well defined.
Methods: This retrospective cohort study included 351 patients (185 males and 166 females) with severe acne who received oral isotretinoin treatment between April 2021 and April 2025. Patients were classified into recurrence and non-recurrence groups according to follow-up outcomes after isotretinoin discontinuation. Baseline demographic characteristics, acne-related clinical features, isotretinoin treatment variables, peripheral sex hormone profiles, and metabolic parameters were collected. Univariate and multivariable logistic regression analyses were used to identify factors associated with recurrence. The combined prediction model was derived from the final multivariable logistic regression model and subsequently evaluated using receiver operating characteristic curve analysis, calibration assessment, and bootstrap internal validation.
Results: During a median follow-up of 20.0 months, 91 patients developed recurrence, with an overall recurrence rate of 25.9%. Multivariate analysis showed that longer disease duration, lower cumulative isotretinoin dose, higher free androgen index, higher dehydroepiandrosterone sulfate, lower sex hormone-binding globulin, higher homeostatic model assessment of insulin resistance, higher triglyceride levels, and lower high-density lipoprotein cholesterol were independently associated with recurrence. Individual hormonal and metabolic indicators showed limited discriminatory ability. The combined prediction model demonstrated better performance, with an area under the curve of 0.824, sensitivity of 76.9%, and specificity of 76.2%. Bootstrap internal validation yielded a corrected area under the curve of 0.812.
Conclusions: Individual hormonal and metabolic markers had limited discriminatory value, whereas a combined model integrating disease duration, cumulative isotretinoin dose, free androgen index, dehydroepiandrosterone sulfate, sex hormone-binding globulin, HOMA-IR, triglycerides, and high-density lipoprotein cholesterol showed better internal performance. Because cumulative dose becomes available during treatment, the model is best regarded as an exploratory dynamic risk-stratification tool; external prospective validation and a clearly defined management pathway are required before routine clinical use.

Keywords:  dehydroepiandrosterone sulfate; free androgen index; metabolic parameters; oral isotretinoin; recurrence; severe acne; sex hormones

DOI:  https://doi.org/10.3389/fendo.2026.1912708