Huntington's disease (HD) is a devastating neurodegenerative disorder characterized by the expansion of cytosine-adenine-guanine (CAG) repeats within the huntingtin (HTT) gene. Given their therapeutic potential, small-molecule strategies have gained significant traction, leading to the design of numerous lead candidates aimed at diverse pathological hallmarks of HD. These developmental efforts target various facets of the disease, including the inhibition and degradation of mutant huntingtin (mHTT) proteins, alleviation of motor dysfunction, and the provision of neuroprotective effects. For instance, gossypol acetate has been identified to induce the autophagic degradation of mHTT. Furthermore, these small molecules modulate critical signaling pathways within HD neurons, such as the store-operated calcium (SOC) channels, dopamine- and cAMP-regulated phosphoprotein 32 (DARPP-32), ataxia-telangiectasia mutated (ATM)/ataxia-telangiectasia and rad3-related (ATR)-p53 pathway, and the kynurenine (KYN) metabolic pathway. While currently explored small-molecule therapies have demonstrated preclinical efficacy, further clinical investigation is imperative to expand the chemical space of viable HD therapeutics. This review critically summarizes the design, synthesis, and structural motifs of small-molecule candidates, clinically used agents, and antioxidant natural products, providing a structural framework to guide the rational design and development of next-generation anti-HD compounds.

Bisphenol F (BPF) has rapidly emerged as a primary substitute for bisphenol A (BPA) and a ubiquitous environmental contaminant, yet its reproductive toxicity remains poorly understood, particularly at low doses. Here, we demonstrate that oral exposure to BPF (as low as 250 μg/kg) induces ovarian hypertrophy, disrupted follicular architecture and cumulus-oocyte communication, and reduced serum estradiol and progesterone in mice by triggering ferroptosis. Integrating multiomics approaches, we identified NCOA4-mediated ferritinophagy as the central cellular driver of this process. In granulosa cells, pharmacologic inhibition of autophagy and gene silencing blocked NCOA4 phosphorylation, ferritin degradation, iron overload, and ferroptosis. Mechanistically, we reveal a new signaling axis wherein BPF promotes the physical interaction between membrane-associated ERβ and the kinase ATM. This interaction triggers ATM activation and subsequent phosphorylation of NCOA4, thereby accelerating ferritin degradation and iron overload. Structural analysis identifies G2296 as the critical interface residue; importantly, an ATM-G2296A point mutation disrupts the ERβ-ATM interaction and abolishes BPF-induced ferroptosis. These findings elucidate a distinct molecular mechanism of ovarian injury driven by low-dose BPF exposure, underscoring the urgent need to reassess the safety profiles of BPF-containing materials.

Studies of hereditary ataxias (HA) without vertical family history are necessary for designing diagnostic protocols. We described the 20 years' experience of a Brazilian reference service with these cases through a retrospective cohort study of subjects evaluated from 2002 to 2020 in a university hospital. Tests for Friedreich ataxia, alpha-fetoprotein, common dominant ataxias, and brain imaging were the first steps, whereas ataxia Sanger panel, exome or genome sequencings (NGS) were the last ones. The outcomes were: diagnosis; no diagnosis after NGS; or incomplete diagnostic investigation. Diagnoses and diagnostic yields were also presented. 174 subjects started investigation and 120 came to the second visit: 45/120 received a diagnosis, 12/120 finished their investigation without a diagnosis, and 63/120 were incompletely investigated. Higher-than-expected proportions of white subjects and of people coming from small communities were found. Most common diagnoses were Friedreich ataxia, ataxia-telangiectasia, Coenzyme Q10 deficiency, Niemann-Pick type C, ataxia with oculoapraxia type 2, and spinocerebellar ataxia type 2. Thirty-two subjects were investigated by NGS; among them, 5/7 ataxia Sanger panels, 9/17 exome and 1/7 genome sequencings got a molecular diagnosis, with diagnostic yields of 71.4%, 52.9% and 14%, respectively. The high proportion of patients lost to follow-up, cases with incomplete investigation and white individuals suggest problems in the access to healthcare. Exome and Sanger panels were the most efficient methods for reaching a diagnosis. The fact they are not easily available in the public health system is an important barrier to overcome, hopefully soon.

Pulmonary arterial hypertension is a rare diagnosis and, when present with pulmonary arteriovenous malformations, a diagnosis of hereditary haemorrhagic telangiectasia should be considered. This case highlights the difficulties in this form of PH. https://bit.ly/4tAmW9R.

Facial depigmentation may remain clinically unrecognized when obscured by persistent erythema associated with steroid-induced rosacea-like dermatitis (SIRD). We report a 42-year-old woman with Fitzpatrick skin phototype IV and a history of prolonged facial topical corticosteroid use who presented with persistent centrofacial erythema. Clinical examination was consistent with SIRD. Multimodal VISIA imaging revealed findings that were not appreciable under standard visible light: red-channel (RBX®) imaging demonstrated increased vascularity and telangiectasia, while ultraviolet imaging identified patchy depigmentation with a speckled pattern and perifollicular pigment preservation. Linear depigmentation corresponding to prior eyebrow tattooing suggested a Koebner phenomenon. Although advised to discontinue corticosteroids, the patient was lost to follow-up and returned three years later with persistent erythema and progression of depigmentation. Repeat ultraviolet imaging demonstrated an increased extent and partial coalescence of the depigmented areas. The longitudinal evolution, imaging features, perifollicular pigment preservation, and trauma-induced depigmentation were most consistent with evolving vitiligo coexisting with SIRD. Following corticosteroid withdrawal, topical tacrolimus 0.1% ointment was initiated. This case highlights how persistent facial erythema can mask progressive depigmentation and demonstrates the value of multimodal VISIA imaging, particularly red-channel and ultraviolet modalities, in detecting subclinical pigmentary changes, differentiating overlapping disease processes, and documenting disease progression.

Biallelic pathogenic variants in the CTC1 gene are associated with cerebroretinal microangiopathy with calcifications and cysts (CRMCCs), also known as Coats plus syndrome (CPS; OMIM #612199). This rare multisystem condition is characterized by early childhood onset of intracranial calcifications, leukodystrophy and cysts, along with retinal telangiectasia and exudates (Coats disease). We report a woman referred to genetics with complex multisystem clinical manifestations beginning in her 30s and progressing over two decades. In keeping with classical features of the condition, she presented a complex medical history of pathological bone fractures, gastrointestinal ectasias, and premature aging. In addition, she developed progressive thrombotic microangiopathy-associated kidney disease requiring transplantation, suspected liver cirrhosis, and subcutaneous dystrophic calcifications. Exome sequencing identified compound heterozygous likely pathogenic variants in CTC1, consisting of a previously reported missense variant and a novel truncating variant confirmed in trans. Despite clinical features suggestive of premature aging, telomere length analysis demonstrated low-normal values for age, supporting emerging evidence that telomere shortening is not a consistent feature of CTC1-related disorders. This case represents the second confirmed adult-onset CTC1-related disorder and the longest survival to date. The findings suggest that subcutaneous calcifications and progressive renal and multi-organ disease may represent later-onset manifestations of the condition. TMA may be a pathologic feature of the multi-system impacts of this rare disease in adults.

A man in his 20s presented with progressive fatigue and melena, with a history of recurrent epistaxis since adolescence and a positive family history. Evaluation revealed severe iron-deficiency anaemia (haemoglobin 27 g/L) with persistently positive faecal occult blood. Upper gastrointestinal endoscopy demonstrated multiple bleeding telangiectasias in the stomach and duodenum. Cross-sectional imaging of abdomen, thorax and brain identified multisystem arteriovenous malformations involving the liver, lung and brain. Despite repeated argon plasma coagulation and thalidomide therapy, bleeding persisted with ongoing transfusion dependence. Treatment with intravenous bevacizumab and subcutaneous octreotide stabilised haemoglobin and resolved occult gastrointestinal bleeding. A clinical diagnosis of hereditary haemorrhagic telangiectasia was established using Curaçao criteria despite negative genetic testing. This case highlights the importance of recognising hereditary haemorrhagic telangiectasia in unexplained severe anaemia and supports the role of anti-angiogenic therapy in refractory gastrointestinal bleeding.

Dermatofibrosarcoma protuberans (DFSP) is a rare, low-grade cutaneous fibroblastic sarcoma of the dermis that typically presents as a slow-growing red or violet colored plaque. It is classically driven by a collagen type I alpha 1 chain::platelet-derived growth factor subunit B (COL1A1::PDGFB) fusion and is characterized by indolent but locally infiltrative growth with a high risk of local recurrence. Here, we present a 39-year-old woman with a past medical history of breast cancer 1 (BRCA1)/ataxia-telangiectasia mutated (ATM) mutations and invasive lobular carcinoma of the left breast status post bilateral mastectomy, who presented with a tender right calf lump for one year. On physical exam, a well-circumscribed, mobile 2 cm mass was palpated in the right calf without overlying skin changes. Biopsy revealed a CD34-positive, low-grade, cellular, spindle cell neoplasm measuring 2.2 × 1.4 × 0.9 cm, extending to the biopsy margins. Histologically, DFSP is characterized by uniform spindle cells with diffuse CD34 staining. Loss of Rb staining was noted in lesional cells, an atypical finding that initially favored a diagnosis of lipoma over DFSP, complicating the initial differential. Fluorescence in situ hybridization (FISH) analysis for COL1A1 rearrangement was negative, necessitating advanced molecular testing. Solid tumor next-generation sequencing fusion panel identified a COL6A3::PDGFD gene fusion, which accounts for about 2% of DFSP cases. The histologic and molecular findings supported a diagnosis of DFSP with an uncommon translocation. The differential diagnosis included spindle cell lipoma and cellular fibrohistiocytic neoplasm, but these were excluded based on immunohistochemistry and genetic data. Given the extension of lesional cells to biopsy margins, re-excision was performed with negative margins. This case exhibits an atypical presentation of DFSP with a rare COL6A3::PDGFD fusion undetectable by standard FISH, demonstrating the importance of advanced molecular testing in suspected DFSP when FISH is negative for the COL1A1 rearrangement. Additionally, DFSP typically presents on the trunk with overlying skin surface changes, making a calf lesion without cutaneous involvement unusual.

The ability of cancer cells to transition between epithelial and mesenchymal states, a process known as epithelial-to-mesenchymal transition (EMT), is a key driver of cancer metastasis and therapy resistance. While ataxia telangiectasia and Rad3-related (ATR) kinase was originally characterized as a responder to DNA damage and replication stress, recent discoveries implicate a critical role for ATR in EMT and metastasis. Two pivotal studies published in this issue of JCI provide key insights into how ATR intersects with EMT transcriptional reprogramming. Patel et al. demonstrated that ATR prevented R-loop accumulation at EMT-related gene loci, thereby facilitating the transcriptional reprogramming necessary for EMT as well as tumor growth and metastasis. Tu et al. further uncovered a role for ATR in ECM stiffness-induced EMT, which was associated with an immunosuppressive tumor microenvironment. Together, these studies highlight important therapeutic implications for ATR targeting in the context of metastasis and therapy resistance.

Doxorubicin (DOX) is a potent antineoplastic agent, but its clinical application is limited by the life-threatening cardiotoxic effects. Poly(ADP-ribose) polymerase 1 (PARP1) transfers ADP-ribose groups from donor NAD[+] molecules onto target substrates upon oxidative stress, which may promote apoptosis and myocardial injury. The detailed molecular pathways of PARP1 activation, however, remain unclear. Here, we found that reactive oxygen species (ROS) function as signalling molecules to promote CBP-mediated PARP1 lactylation in an ATM-dependent manner, which induces PARP1 PARylation and ultimate cell apoptosis. We identified CBP and SIRT1 as specific lactyltransferase and delactylase of PARP1, respectively. Besides, the lactylation of PARP1 depends on the LDHA activity and lactate production. Moreover, Myocardium-specific CBP knockout mice decrease PARP1 lactylation and prevent doxorubicin-induced cardiac dysfunction. Our findings unravelled that excessive oxidative stress-induced ROS accumulation activates the ATM-CBP-PARP1 signalling pathway via a lactylation-PARylation cascade to promote apoptosis and myocardial injury.