Cellular senescence is a stress response that prevents the proliferation of damaged cells. As senescence has evolved in the near-surface biosphere, where cosmic background radiation (CBR) continuously delivers a low flux of highly penetrating muon particles, we investigated whether this persistent abiotic stress contributes to senescence thresholding. At the Canfranc Deep Underground Laboratory, an astrophysical facility located 800 meters beneath granite rock in the Spanish Pyrenees (~2,450 meters of water-equivalent depth), cosmic muons are suppressed by five orders of magnitude. There, we examined the senescence-induction dynamics in human cancer cells exposed to G0/G1- or G2/M-targeting chemotherapeutics and compared them to cells in adjacent, above-ground conditions with natural CBR. Muon depletion significantly reduced the acquisition of the senescence-associated β-gal-positive phenotype under conditions favoring a G0/G1 arrest with the CDK4/6 inhibitor palbociclib. SA-β-gal-positive states driven by G2/M arrest in response to the mitotic kinase inhibitor alisertib and the DNA-damaging radiomimetic bleomycin were insensitive to muon suppression. While the SENCAN classifier, which uses RNA-seq data to determine whether cell samples are senescent, and the senescence-associated secretory phenotype profiles were largely unaffected by the absence of cosmic-ray muons, muon depletion caused small variations at a transcriptome-wide level in the two pathways to senescence. Our hypothesis-generating study suggests that muons might act as abiotic signal-to-noise calibrators that facilitate the consolidation of senescence trajectories specifically associated with G0/G1 withdrawal. Our exploratory findings shed light on how life incorporated CBR evolutionarily to sense and respond to cellular damage, which could inform senescence operability in low-muon extraterrestrial habitats.
Approximately 10% of cosmic spherules-microscopic extraterrestrial particles that melt upon atmospheric entry and dominate the influx of astromaterials to Earth-exhibit anomalous oxygen isotopic compositions, suggesting an asteroidal source not represented in current meteorite collections. We introduce a a previously unidentified subset of micrometeorites, the sulfur-rich cumulate olivine (SCumPo) cosmic spherules, characterized by cumulate textures evidencing the settling of olivine crystals, and oxygen-16 (16O)-poor bulk signatures. The systematically nickel-poor olivine phenocrysts, frequent iron-nickel-sulfur droplets, unusually sulfur-rich mesostasis, and a virtual absence of magnetite all point to unusually highly reducing conditions during atmospheric entry, which may reflect unusual precursor mineralogy. Numerical modeling of olivine settling under deceleration speeds of ~14 to 17 kilometers per second suggests high-eccentricity precursor orbits (e > 0.2), incompatible with typical main-belt asteroid sources. These findings point to a previously unsampled, primitive, sulfide-rich CY-like near-Earth asteroid, which represents a "missing" meteorite parent body that contributes distinctive 16O-poor cosmic dust to Earth.
We investigate the propagation of ultraheavy (UH) nuclei as ultrahigh-energy cosmic rays (UHECRs). We show that their energy loss lengths at ≲300  EeV are significantly longer than those of protons and intermediate-mass nuclei, and that the highest-energy cosmic rays with energies beyond ∼100  EeV, including the Amaterasu particle, may be UH-UHECRs. For the first time, we derive constraints on the contribution of UH-UHECR sources, and find that the current data are consistent with energy generation rate densities of UHECRs from collapsars and neutron star mergers. Our model predicts that the mean value of the depth of shower maximum is lower than that for iron nuclei beyond 100 EeV, which can be tested with future composition measurements, e.g., AugerPrime and the Global Cosmic Ray Observatory. In addition, the spectral tension between the Telescope Array (TA) and the Pierre Auger Observatory can be alleviated by considering the enhanced contribution of UHECRs-including UH nuclei-from a nearby transient.
Galaxy redshift surveys map the cosmic web and provide a key observational test of whether the Universe becomes statistically homogeneous and isotropic on sufficiently large scales, as assumed by the cosmological principle underpinning the standard cosmological model1. In this framework, beyond the nonlinear regime of structure formation, inhomogeneous and anisotropic features are expected to fade rapidly, reflecting the near-isotropic primordial density field and its subsequent gravitational evolution. Although supported by the small amplitude of cosmic microwave background anisotropies2, this view is increasingly challenged by the complex network of large-scale structures and voids in the galaxy distribution3-6, as well as by independent probes reporting possible large-scale deviations from statistical homogeneity7 and isotropy8,9. Here we show that the galaxy distribution exhibits persistent anisotropic structures extending to scales on the order of one gigaparsec. Using the Angular Distribution of Pairwise Distances (ADPD)10, a parameter-free statistic that measures directional correlations, we detect anisotropy signals exceeding those in isotropic controls and geometry-matched ΛCDM mock catalogues with conservative significance greater than 3σ. These results provide direct evidence that directional coherence persists to larger scales than predicted in the standard framework, challenging the assumption of large-scale isotropy. They call for a reassessment of how homogeneity and isotropy are realized in the observed Universe and motivate new tests of cosmological models based on directional statistics.
DNA methylation aging clocks are among the most accurate biomarkers of chronological and biological age, yet why the methylome encodes time with reproducible precision remains unclear. Current models emphasize developmental patterning, imperfect epigenetic maintenance, chromatin drift, and remodeling associated with DNA repair. However, they do not consider whether the persistent physical noise from Earth's radiation environment contributes to clock variance or coherence. Here, we propose DEEP-CLOCK, an experimental framework that uses the deep underground laboratory (LSC-DUL) at Canfranc (Spain) as a natural protector from a primary external stochastic input, namely surface-level cosmic-ray muons. DULs suppress the muon component of cosmic-ray background radiation by several orders of magnitude without eliminating endogenous biochemical noise and other radiation sources. This enables DNA methylation clocks to be interrogated as noise-limited biosensors by measuring mean epigenetic-age trajectories, clock-CpG variance, and methylation entropy under matched underground and above-ground conditions. Two outcomes are envisioned. Muon depletion may narrow clock variance while preserving the mean trajectory, which is consistent with improved timekeeping precision. Alternatively, muon depletion could reveal structured drift, altered slopes, or metastable offsets, suggesting that extreme radiobiological quietness could destabilize clock coherence. Neither outcome would by itself imply slowed aging, rejuvenation, or improved function alone. However, DEEP-CLOCK will test whether epigenetic clock behavior is fully intrinsic or partly calibrated by chronic low-dose radiobiological background. This reductionist framework could clarify the physical constraints on epigenetic timekeeping and inform how aging clocks function in shielded terrestrial, lunar, and Martian habitats during aging, disease, and future space habitation.
In this paper for the first time the frequency of complex double strand breaks (DSB) and non-DSB clustered damage behind spacecraft and tissue shielding from exposure to galactic cosmic rays (GCR) and secondary radiation are predicted. Elementary DNA lesions produced by ionizing radiation include single strand breaks (SSB) and various forms of base damages (BD) (e.g. abasic or oxidative sites). Clustered DNA damage is defined by the occurence of 2 or more elementary lesions within 10 base-pairs (bp), and complex clustered damage as 3 or more elementary lesions within 10 bp. Clustered DNA damage is more difficult to repair compared to simple forms of DNA damage, while the relative contribution of clustered to simple DNA damage increases with ionization density or linear energy transfer (LET), and therefore imporant for space radiation exposures. The author has developed the multinominal model of clustered DNA damage that uses nanoscopic energy imparted spectra in DNA volumes and damage location probability operators to predict clustered DNA damage frequencies. In this paper, I combine the results of the multinomial model with GCR particle energy spectra to predict the probabilities of complex DSB, and tandem and bistranded non-DSB clustered damage. Predictions for the local interstellar (LIS), solar mininum, and solar maximum environments are discussed. Results show that the frequency of DSB and non-DSB clusters attenuates slowly with aluminum and tissue shielding, and that non-DSB clusters are >4 times more frequent than prompt DSBs. This is an important finding which quantifies a prediction of the dominance of delayed formation of DSBs created in non-DSB clusters repair processes over prompt DSBs in the initial GCR DNA damage in tissues.
High-energy heavy-ion particle accelerators have long served as proxies for the harsh space radiation environment, enabling both fundamental life-science research and applied testing of flight hardware. Traditionally, monoenergetic high-energy heavy-ion beams have been employed for practicality, providing valuable datasets that underpin radiation risk and predictive computational models. However, such beams cannot fully reproduce the mixed-field nature of space radiation, motivating the development of realistic analogs for improved risk assessment and countermeasure evaluation in preparation for future deep-space missions to Moon or Mars. Spearheaded by developments at the NASA Space Radiation Laboratory, the GSI Helmholtzzentrum für Schwerionenforschung, supported by the European Space Agency (ESA), has established advanced space radiation simulation capabilities in Europe. Here, we present the design, optimization, and in-silico benchmarking of GSI's hybrid active-passive Galactic Cosmic Ray (GCR) simulator, together with a computationally optimized phase-space particle source for Geant4, which is available to external users for their own simulation studies and experimental planning.
Galactic cosmic rays (GCR) are a principal source of ionizing radiation exposure for astronauts during deep space missions. Given the ambition to expand manned space exploration to distant destinations like Mars, it is essential to accurately predict the radiation doses astronauts are likely to encounter and the consequent biological impacts. Accurate dose predictions are important for operational radiation safety, ensuring that risk assessments and protective measures are appropriately calibrated to the myriad of challenges of deep space travel. The GCRsim facility at the NASA Space Radiation Laboratory enables small animal radiobiology studies of GCR exposure, offering a controlled setting to mimic the complex radiation conditions found in deep space. This manuscript introduces a series of Dose Conversion Factors (DCFs) which enable rigorous absorbed dose calculations for mice irradiated at the GCRsim. A formalism was introduced for calculating organ-level and voxel-level radiation dose to a representative mouse phantom, based on DCFs quantifying radiation absorbed dose per unit fluence of different GCRsim beam components for different irradiation orientations. The PHITS Monte Carlo code was employed to compute the DCFs in units of Gy∙cm2∙ion-1. A library of murine DCFs were derived using the PHITS Monte Carlo code for six irradiation orientations: right-left, anterior-posterior, superior-inferior, and their opposed variations. Absorbed doses to the murine total body were calculated with the method and compared with ion chamber measurements, which agreed within 10 %. A library of dose conversion factors for mouse irradiation at GCRsim was developed and validated against physical measurements. These DCFs account for organ-specific variations in radiation dose from different GCRsim beam components, enabling improved assessments of potential radiogenic effects, toward improving astronaut safety measures for future deep space missions.
Space radiation is one of the major obstacles to space exploration. If not mitigated, radiation can interact both with biological and electronic systems, inducing damage and posing significant risk to space missions. Countermeasures can only be studied effectively with ground-based accelerators that act as a proxy for space radiation. Following an in-silico design and optimization process, we have developed a galactic cosmic ray (GCR) simulator using a hybrid active-passive methodology. In this approach, the primary beam energy is actively switched and the beam interacts with specifically designed passive modulators. In this paper, we present the implementation of such a GCR simulator and its experimental microdosimetric characterization. Measuring the GCR field is of paramount importance, both before providing it to the user as a validated radiation field and for achieving the best possible radiation description. The issue is addressed in this paper by using a tissue equivalent proportional counter to measure radiation quality and by comparing experimental measurements with Monte Carlo simulations. In conclusion, we will demonstrate the GCR simulator's capability to reproduce a GCR field.
Lipid peroxidation products modify proteins during oxidative stress, but the residue-pair connectivity and structural consequences of these reactions remain difficult to define. Here, we redefine the lipid peroxidation product 4-oxo-2-nonenal (4-ONE) from a damaging electrophile into a chemoselective Cys-Lys covalent crosslinker. Through a chemoselective, two-step pathway, Michael addition to cysteine activates a latent aldehyde that cyclizes with lysine to form a stable pyrrole linkage under physiological conditions. We show that this chemistry supports late-stage peptide functionalization, macrocyclization and stapling, selective protein modification, and proteome-wide mapping of 4-ONE-reactive lysine and cysteine residues. Additionally, late-stage oxidation converts this pyrrole linkage into an MS-cleavable sulfoxide for site-resolved identification of linked residues through diagnostic link-site-containing fragments, a workflow we name COSMIc (Crosslink Oxidation to Sulfoxide for Mass-Cleavable Interactomics). COSMIc enables detection of structurally informative crosslinks in the human 26S proteasome, where peroxide-induced sulfoxide formation markedly improves fragment assignment and residue-pair confidence. Together, these findings repurpose 4-ONE from a toxic electrophile into a compact, metabolite-derived Cys-Lys crosslinker for covalent mapping and structural proteomics.
Particle nucleation from trace atmospheric vapours is important for climate since it gives rise to more than half of global cloud condensation nuclei. Sulfuric acid (H2SO4) has long been recognised to drive particle nucleation in the atmosphere and, more recently, highly oxygenated products of biogenic vapours-in particular monoterpenes such as α-pinene (C10H16)-have also been shown to nucleate under atmospheric conditions, without requiring additional vapours. This raises the question of whether a nucleation synergy exists between α-pinene oxygenated organic molecules (AP-OOM) and H2SO4, as has been suggested by early studies. Here we report new particle formation from AP-OOM and H2SO4 in the absence of base vapours such as ammonia (NH3), measured in experiments performed with the CERN CLOUD (Cosmics Leaving Outdoor Droplets) chamber at cool boundary layer temperatures of -10 °C and +5 °C. We find that AP-OOM nucleation rates increase strongly when H2SO4 concentrations exceed around 106 cm-3. The enhancement is synergistic and cannot be explained as a simple linear addition of independent chemical systems. Above this threshold, the nucleation rate depends approximately linearly on H2SO4 concentration, in contrast with the strong sensitivity to H2SO4 for H2SO4-NH3 nucleation. Nucleation rates are 10-100-fold higher in the presence of ions from galactic cosmic rays or from the CERN pion beam. Based on these measurements, we have parameterised a temperature-dependent H2SO4-AP-OOM nucleation rate in the absence of base vapours and implemented it in the EMAC (ECHAM/MESSy Atmospheric Chemistry) Earth system model. In comparison with a parameterisation developed in an earlier study [Riccobono et al., Science, 2014, 344, 717-721.], the new parameterisation indicates sharply reduced nucleation rates in the boundary layer over warm regions, and increased rates over northern boreal forests.
Proper consideration of the relative biological effectiveness (RBE) is essential for evaluating potential health risks associated with exposure to cosmic radiations spanning a broad range of linear energy transfer (LET). The quality factor as a function of LET, Q(L), empirically proposed and refined by the International Commission on Radiological Protection (ICRP), remains central to assessments of relatively low-dose cosmic radiation exposures, despite the primary use of radiation weighting factors (wR) in terrestrial protection frameworks. This article reviews the historical development of the Q(L) function and examines the adequacy of its application to cancer risk analysis. To this end, we first confirm its numerical consistency with a more sophisticated quality factor algorithm adopted by NASA through a comprehensive literature review. We then evaluate the appropriateness of the maximum value of Q(L), using a meta-analysis of RBE data for mouse tumor induction by fission neutrons. Finally, we discuss future perspectives on Q(L), emphasizing its strong relevance to measurements not only in space dosimetry but also in medical physics.
Collisionless shocks are ubiquitous in space plasmas throughout the Universe and are widely believed to be primary sites of cosmic ray acceleration1,2. The prevailing mechanism, diffusive shock acceleration, requires particles to repeatedly cross the shock front, gaining energy with each crossing. The maximum achievable energy is fundamentally constrained by the Hillas criterion, which relates the physical scale of the accelerator to the maximum particle energy3. However, the scarcity of direct observational constraints for acceleration sites limits our ability to predict maximum particle energies across most astrophysical systems. Here, using data from the Juno spacecraft of NASA, we show the direct evidence of relativistic electron acceleration (≥1 MeV) upstream of the bow shock of Jupiter, powered by a large-scale foreshock transient4,5. Leveraging these and complementary Solar System observations, we propose a universal scaling law for the Hillas limit that empirically connects the observable size of a transient to maximum particle energy. Applying this scaling to various environments, from planetary bow shocks6 to protostellar jets7 and supernova remnants8, yields a simple model of maximum obtainable particle energies ranging from MeV scales up to about tens of GeV, and about tens of TeV, respectively, providing an observationally grounded method for constraining maximum cosmic ray energies at astrophysical shocks9,10.
Long-duration space missions pose a considerable risk to eye health, and visual dysfunction is recognized as a primary health concern for astronauts. Hence, we have developed a series of review reports to study the effects of space on the eye, called AstroOphthalmology (including Basics, Ocular Anterior Segment, Ocular Posterior Segment). This report serves as the first report of our series, and integrates the current insights into the pathophysiological consequences of the space environment on the eye. The two key space-specific stressors include microgravity and cosmic radiation. Both stressors are the interconnected pathways of oxidative stress and mitochondrial dysfunction, which inflict damage on cellular components and disrupt the function of essential ocular tissues. Microgravity triggers a cephalad fluid shift, which leads to vascular congestion, changes in hemodynamics, and increased intracranial pressure. The aforementioned changes are considered to be culprits in the onset of spaceflight-associated neuro-ocular syndrome (SANS). Exposure to galactic cosmic radiation and solar particle events presents a substantial risk for the formation of cataracts, retinal cotton-wool spots, and optic neuropathy. This review indicates that ocular damage during spaceflight is influenced by multiple factors, resulting from the synergistic interaction of fluid shifts and radiation. In addition to pathophysiology, we summarize the current in-flight evaluations such as optical coherence tomography and fundoscopy. Future research should focus on assessing combined countermeasures and establishing predictive biomarkers to mitigate these risks, which is imperative for the success of future lunar and Martian missions.
The solar system currently traverses the Local Interstellar Cloud (LIC), one of several warm cloudlets of the Complex of Local Interstellar Clouds (CLIC) in the solar neighborhood. The origin of these cloudlets is unknown and could be related to supernova shock wave dynamics. If supernovae are the source of these cloudlets or influence their properties, the CLIC may act as a cosmic archive for the supernova-produced radionuclide ^{60}Fe. We detected minuscule traces of interstellar ^{60}Fe in 295 kg of the European Project for Ice Coring in Antarctica Dronning Maud Land ice core, covering the time period 40-81 kyr ago. We find an ^{60}Fe/^{53}Mn ratio of (8±5)×10^{-4}, slightly above the expected cosmogenic production, corresponding to an interstellar deposition rate of (0.22_{-0.12}^{+0.14}) ^{60}Fe at/cm^{2}/yr. This influx is significantly lower than that observed in recent Antarctic snow and marine sediment records during the last 40 kyr. These results suggest that the LIC is a cosmic archive for supernova-produced ^{60}Fe. The imprinted ^{60}Fe time profile is evidence for a changing local interstellar environment over the last 80 kyr.
Dimethylsulfide (DMS; CH3SCH3) from marine phytoplankton is a major source of atmospheric sulfur 1. Its oxidation products include sulfuric acid (SA; H2SO4) and methanesulfonic acid (MSA; CH3SO3H), which has a higher yield than SA below 10 °C 2. Whereas SA is known to drive the formation of new particles 3, which may subsequently grow and act as cloud condensation nuclei (CCN), the role of MSA remains unclear 4. Here, in experiments performed under atmospheric conditions at the CERN CLOUD (Cosmics Leaving OUtdoor Droplets) chamber, we show that MSA nucleates together with ammonia (NH3) below -10 °C, at rates comparable to SA-NH3. Moreover, MSA and SA nucleate synergistically below -10 °C, forming multi-acid molecular clusters with NH3. Even at ultra-low NH3 levels, MSA drives particle growth at or near the kinetic limit below 9 °C and above 40 % relative humidity (RH). Since MSA and SA generally coexist at similar concentrations in cool marine regions, our findings indicate that nucleation rates may be accelerated up to tenfold and growth rates up to twofold compared with SA-NH3 alone. Our global model simulations indicate that MSA can enhance CCN concentrations, especially in polar regions. We propose that MSA might be an important driver of biogenic particles in cool, pristine marine regions of both the present-day and pre-industrial atmospheres, and yet is unaccounted for in global climate models 5.
Long-term deep space missions present critical health challenges due to prolonged exposure to space radiation and microgravity, leading to significant physiological risks for astronauts. Galactic cosmic rays, in particular, can penetrate conventional shielding and produce harmful secondary particles, emphasizing the need for innovative in-situ solutions to study the effects of these environmental conditions on astronauts' health and mitigate the risks. We have developed an advanced lab-on-chip system designed for real-time monitoring and precise environmental control, which allows us to detect changes in living cells throughout a long-term space mission. The system is equipped with integrated photo and thermal sensors based on hydrogenated amorphous silicon functional layers and resistive heating elements for continuous environmental monitoring and precise temperature regulation. By using a modular and adaptable fabrication approach-combining laser-cut polymethyl methacrylate components, adhesive bonding, and thin-film integration-our design enables rapid prototyping and customization for various mission needs. Our platform features a tapered culture chamber that employs both passive and active fluid management techniques to maintain stable liquid positioning. This is achieved through feedback-controlled pressure modulation, addressing the unique challenges of fluid dynamics in space. We validated the system through a series of simulations and experiments demonstrating effective fluid management and accurate environmental control, essential for future biological research in space. Our results underscore the potential of this low-power, automated, and highly compact lab-on-chip solution to advance the study of space radiation effects and contribute to safer, long-duration crewed missions.
Dissipative dynamics across physical systems exhibit organizing structural boundaries. The dimensionless damping ratio [Formula: see text] defines a stability architecture in which the critical threshold [Formula: see text] marks a second-order non-Hermitian Exceptional Point (EP2). Within spatially flat ΛCDM, an exact algebraic identity is demonstrated linking the onset of cosmic acceleration to critical damping of structure growth: [Formula: see text]. This identity is a structural reformulation of the standard Friedmann and growth equations, not a new physical law; its scientific value lies in recasting a known kinematic transition as a stability-phase transition and in generating the falsifiable prediction that departures from flat ΛCDM produce a measurable, nonzero offset between the [Formula: see text] and [Formula: see text] transitions (identically zero under flat ΛCDM, generically nonzero in extensions). A substrate inheritance relation is then proposed as a leading-order projection approximation, whereby emergent modes acquire effective parameters from substrate precursors. Within this framework, the observed particle distribution is consistent with stability organization: long-lived matter occupies localized stability basins at [Formula: see text], while short-lived resonances occupy a secondary [Formula: see text]-1 band whose sub-cluster evidence is suggestive rather than conclusive. The framework is presented as a structurally grounded classification with defined scope and testable consequences.
Salvia hispanica L. (chia) microgreens are recognized as nutrient-dense crops suitable for controlled-environment agriculture but never been tested for space-related applications. Elucidating the physiological and biochemical responses of plants to ionizing radiation is essential for crop selection in space agriculture. Ground-based studies, employing irradiation of seeds with heavy ions as components of Galactic Cosmic Rays, are needed to identify radiation-tolerant crops suitable for long-duration missions. This study aimed to evaluate the effects of carbon (12C) and iron (56Fe) ions, on the morphological, anatomical, and biochemical traits of chia microgreens, as a candidate, emerging crop, for space cultivation. Dry seeds were irradiated with five doses (0.3, 1, 10, 20, and 25 Gy) of each ion type, and responses were assessed at the seedling stage. Distinct ion-specific and dose-dependent responses were observed across multiple functional traits. Iron irradiation promoted shoot elongation, photosynthetic pigment and soluble protein contents, whereas carbon ions increased seedling transpiration, nutrient accumulation (K, Mg, Ca), and polyphenol content, accompanied by notable anatomical adjustments in leaf tissues. Despite these structural and biochemical adjustments, net photosynthesis remained unaffected by irradiation treatments. However, PN contributed to sample separation in the PCA through its covariation with other morpho-physiological and biochemical traits. Phenotypic plasticity analysis revealed higher responsiveness of biochemical traits than anatomical ones, particularly under iron ion exposure. Overall, the ability of S. hispanica microgreens to preserve photosynthetic performance, while modulating key functional traits under ionizing radiation, underscores their physiological plasticity and provides evidence supporting their potential suitability for space-based cultivation systems.
Hepatocellular carcinoma (HCC) represents a major health burden, historically treated with tyrosine kinase inhibitors (TKIs). The advent of immune checkpoint inhibitors (ICIs) has reshaped treatments, with pivotal trials (IMbrave150 and HIMALAYA) establishing ICI-based combinations as first-line therapy. Traditional statistical metrics may not fully capture the robustness of trial outcomes. The Survival-Inferred Fragility Index (SIFI) quantifies trial stability as the minimum number of additional survival events required to lose statistical significance. We systematically searched PubMed, Embase, Scopus for phase III randomized controlled trials comparing ICIs and TKIs in HCC published up to 31 May 2025. Trials reporting statistically significant time-to-event outcomes were included. Individual survival data were reconstructed from Kaplan-Meier curves using validated methods, SIFI was calculated using specific R algorithms. Six trials (4570 patients) were included for primary analysis (IMbrave150, COSMIC-312, ORIENT-32, CARES-310, HIMALAYA; CheckMate 9DW analyzed separately for its heterogeneous control arm). Median SIFI was 10 (range 5-18) for overall survival, 8 (range 6-19) for progression-free survival. SIFI corresponded to <1% of enrolled patients in most trials. Asian- trials (ORIENT-32, CARES-310) showed higher stability (SIFI 16-20) compared to global trials. SIFI analysis revealed heterogeneous stability across pivotal HCC trials. Incorporating fragility metrics with conventional statistics may improve interpretation and support balanced interpretation of trial outcomes.