Second Affiliated Hospital of Harbin Medical University

Aberrant lysine 2-hydroxyisobutyrylation (Khib) is a novel post-translational modification implicated in tumor progression, but its role in intrahepatic cholangiocarcinoma (ICC) remains poorly defined. Here, we identify a specific Khib modification at lysine 97 (K97) of the oncogenic transcription factor ETV4, which is significantly upregulated in ICC and strongly associated with tumor metastasis and poor patient outcomes. Functional assays demonstrate that ETV4 K97-Khib enhances ICC cell proliferation, invasion, and distant metastasis by promoting ferroptosis resistance. Mechanistically, ETV4 K97-Khib represses transcription of the ferroptosis inducer TXNIP and simultaneously facilitates its post-translational degradation through upregulation of the SUMO E3 ligase ZBED1, leading to increased SUMOylation of TXNIP. This dual mechanism reduces TXNIP levels and potently suppresses ferroptosis. KAT2A and HDAC1 were identified as the acyltransferase and deacylase controlling ETV4 Khib dynamics, respectively. Notably, the small-molecule compound thiostrepton significantly inhibits ETV4 K97-Khib, thereby promoting ferroptosis and suppressing ICC cell migration, invasion, and lung metastasis. Together, our study reveals a novel ETV4 Khib-driven mechanism underlying ferroptosis suppression and malignant progression in ICC, and highlights ETV4 Khib as a potential therapeutic target in cholangiocarcinoma.

The Halo sign is a recently identified slit-lamp optical phenomenon observed in keratoconus. This study aims to systematically characterize this phenomenon and investigate its clinical features in eyes with keratoconus. This retrospective, observational case series included 11 consecutive patients (22 eyes) with a clinical diagnosis of KC from a single tertiary center. Slit-lamp biomicroscopy with the beam directed at the cone apex was performed to evaluate the presence of the Halo Sign. A quantitative Halo Morphology Index (HMI) was defined as the aspect ratio (major/minor axis; a/b) of an ellipse fitted to the segmented halo outline on slit-lamp photographs and measured in ImageJ. Clinical and imaging characteristics were summarized descriptively, including corrected distance visual acuity (CDVA, logMAR), Amsler-Krumeich (AK) stage, thinnest corneal thickness (Thk), keratometric indices (e.g., mean corneal refractive power and mean pupillary power), keratoconus vertex distance (KVD), and corneal higher-order aberrations (HOAs). AS-OCT structural staging was recorded when gradable. The Halo Sign was absent in 14 eyes and present in 8 eyes. Halo-positive eyes were predominantly advanced by AK staging (all 8 eyes were AK stage 4), whereas Halo-negative eyes spanned a wider range of AK stages (1–4). In descriptive comparisons, Halo-positive eyes tended to have worse CDVA (logMAR), thinner corneas, steeper keratometry, and a higher prevalence of corneal scarring than Halo-negative eyes. Cone decentration (KVD) was also greater in Halo-positive eyes. AS-OCT structural staging was available in 19/22 eyes, with Halo-positive eyes more frequently classified as Sandali OCT stage 2 than Halo-negative eyes. HMI values in Halo-positive eyes ranged from 1.07 to 3.93, reflecting increasing halo outline anisotropy/irregularity. The Halo Sign is a newly described slit-lamp optical phenomenon that was observed predominantly in advanced keratoconus in this exploratory case series. HMI provides an operational, image-based descriptor of halo outline anisotropy.