About

Ian A. Blair, Ph.D., is the A.N. Richards Professor of Pharmacology at the University of Pennsylvania School of Medicine. He is an investigator at the Abramson Cancer Center and a member of the Institute for Medicine and Engineering, the Genomics Institute, and the Institute for Translational Medicine and Therapeutics at the University of Pennsylvania. Dr. Blair directs the Program in Systems Biology within the Institute for Translational Medicine and Therapeutics and is involved in multiple research initiatives related to proteomics, DNA-adductomics, metabolomics, and lipidomics, with a focus on discovering biomarkers for early cancer detection and response in rare diseases. His research expertise includes establishing high-resolution mass spectrometry and molecular biology as tools for sophisticated biomarker discovery. His work emphasizes understanding danger-associated molecular pattern (DAMP) molecules such as Amyloid β-peptides and high-mobility group box 1 (HMGB1), particularly their roles in immune signaling and their potential as biomarkers in cancer and environmental exposure contexts. Dr. Blair has developed methodologies for quantifying HMGB1 proteoforms in plasma samples from patients with mesothelioma, non-small cell lung cancer, and asbestos exposure, as well as quantifying lipid hydroperoxide-mediated DNA damage in lymphocytes. Additionally, Dr. Blair's research extends to biomarkers of therapeutic response in rare genetic diseases, including Duchenne’s muscular dystrophy, Friedreich’s ataxia, and spinocerebellar ataxia 1. His strategies involve monitoring protein expression and mitochondrial metabolism to evaluate treatment efficacy, aiming to improve diagnostic and therapeutic approaches for these conditions. His contributions are characterized by a focus on translational research that bridges molecular biology, analytical chemistry, and clinical applications.

Research topics

• Oncology
• Chemistry
• Biochemistry
• Genetics
• Cell biology
• Biology
• Internal medicine
• Medicine
• Cancer research

Selected publications

• HMGB1 and HMGB2 proteins in ferroptosis, cancer, and neurodegeneration

  Medical Research Archives · 2026-01-01

  articleOpen access1st authorCorresponding

  Introduction High mobility group box (HMGB) proteins are nuclear DNA-binding factors that, once released from the nucleus, behave as damage-associated molecular patterns (DAMPs) capable of activating pattern recognition receptors (PRRs). The role of HMGB1 in cell death has been characterized in considerable detail, whereas HMGB2 has only lately been linked to immunogenic cell death (ICD) and ferroptosis. Clarifying how these closely related proteins differentially control oxidative forms of cell death has important implications for both cancer and neurodegenerative disease. Methods In this review, we have assembled recent mechanistic, cellular, and translational data on HMGB1 and HMGB2, with particular emphasis on studies that delineate their structural features, XPO1-dependent nuclear export, and downstream signaling networks in ferroptosis, cancer immunogenicity, and neurodegeneration. We highlight (in particular) quantitative proteomic, genetic, and pharmacologic experiments that differentiate HMGB1- from HMGB2-driven functions. Conclusion HMGB1 and HMGB2 occupy distinct yet complementary, positions at the crossroads of oxidative stress, ferroptosis, and inflammatory signaling. Signaling events that depend on nuclear export of these proteins govern chemotherapy-induced immunogenic cell death in cancer as well as contributing to chronic neuroinflammation and neuronal loss. Targeting HMGB-centered pathways, including XPO1-mediated export, with novel therapeutic strategies may therefore open new avenues for cancer immunotherapy and for neuroprotective interventions.

  PublisherOA PDFDOI

• Safety and efficacy of individualised exercise and NAD+ precursor supplementation in patients with Friedreich's ataxia in the USA: a single-centre, 2 × 2 factorial, randomised controlled trial

  The Lancet Neurology · 2026-04-17 · 1 citations

  articleOpen access

  BACKGROUND: precursor supplementation with nicotinamide riboside, which have each shown benefits in animal and early clinical studies, on cardiopulmonary fitness in individuals with Friedreich's ataxia. METHODS: . Stage 1 analysis tested the difference between each active treatment versus the control group, and stage 2 analysis (if combination therapy was effective) tested the difference between combination treatment and exercise alone; family-wise type 1 error was maintained <0·05. Analyses were by intention-to-treat. Adverse events were recorded systematically. This trial is registered with ClinicalTrials.gov (NCT04192136) and is complete. FINDINGS: =0·0299) for nicotinamide riboside and exercise in combination. Combination therapy was not statistically different from exercise alone (difference -0·05 ([95% CI -0·10 to 0·21]; p=0·49). Adverse events were all mild or moderate, and included gastrointestinal symptoms, falls, upper respiratory infections, and skin rashes. At least one moderate adverse event of interest in these categories was reported by seven (41%) participants in the control group; six (35%) in the nicotinamide riboside and no exercise group; three (19%) in the placebo and exercise group; and four (25%) in the nicotinamide plus exercise group. INTERPRETATION: The combination of nicotinamide riboside plus exercise for 12 weeks was safe and increased cardiopulmonary fitness in children and adults with Friedreich's ataxia. Longer studies are needed to establish whether adding nicotinamide riboside to exercise could be considered as part of a long-term, comprehensive treatment approach. FUNDING: US National Institutes of Health and Friedreich's Ataxia Research Alliance.

  PublisherDOI

• Therapeutic activity of a hematopoietic stem cell-delivered cell-penetrating frataxin in Friedreich’s ataxia models

  Cell Reports Medicine · 2026-05-01

  articleOpen access

  HSPCs transduced with the vector differentiated normally into macrophages and secreted the peptide. These results support a cell and gene therapy strategy for long-term stabilization of FRDA.

  PublisherDOI

• Peripheral frataxin levels govern long-term clinical progression in Friedreich ataxia

  BMJ Neurology Open · 2026-01-01

  articleOpen access

  Background: Novel therapeutics for Friedreich ataxia employ diverse strategies to increase frataxin protein levels, and a better understanding of the relation to clinical outcomes could strengthen their use as pharmacodynamic markers, and potentially as surrogate endpoint in therapeutic development. An elaborate modelling framework was developed to evaluate the suitability of frataxin as a biomarker across assays, tissues and disease stages. Methods: Frataxin levels generated previously through two distinct assay platforms and from two separate clinical cohorts: whole blood frataxin was measured by a lateral-flow immunoassay (LF cohort), and a triple-quadrupole LC-MS/MS method (TQ cohort), which enables separate quantification of mature frataxin (FXN-M) and erythrocyte-specific frataxin (FXN-E). Results were compared descriptively with control and heterozygous carriers, and several distinct modelling strategies were employed to correlate them with clinical function. Results: Both cohorts represented the relevant disease spectrum, with minor differences in both genetic and clinical severity, which correlated with frataxin levels. Heterozygous carriers showed intermediate levels. Modelling confirmed the predictive value of frataxin across multiple clinical assessments, such as age of symptom onset, age at loss of ambulation and long-term progression. GAA1, the shorter repeat expansion, was confirmed as the dominant predictor of frataxin itself, and, in most situations, clinical function. Discussion and conclusion: Although isoform biology and tissue-specific expression remain important considerations, peripheral frataxin quantification provides biologically grounded measure of the pathophysiology and disease progression, with strong potential for application in therapeutic trials. Frataxin is a valid clinical biomarker, and our findings support advancing its candidacy as a surrogate endpoint in Friedreich ataxia.

  PublisherOA PDFDOI

• Author Correction: HMGB2-induced calreticulin translocation required for immunogenic cell death and ferroptosis of cancer cells are controlled by the nuclear exporter XPO1

  Communications Biology · 2025-10-04

  erratumOpen accessSenior author
  PublisherOA PDFDOI

• Technical recommendations for analyzing oxylipins by liquid chromatography–mass spectrometry

  Science Signaling · 2025-05-20 · 30 citations

  reviewOpen access

  Several oxylipins are potent lipid mediators that regulate diverse aspects of health and disease and whose quantitative analysis by liquid chromatography-mass spectrometry (LC-MS) presents substantial technical challenges. As members of the lipidomics community, we developed technical recommendations to ensure best practices when quantifying oxylipins by LC-MS.

  PublisherOA PDFDOI

• Stable Isotope Labeling in Bacteria Enables Characterization and Quantification of Frataxin Protein in a Friedreich’s Ataxia Zebrafish Model

  Analytical Chemistry · 2025-06-24 · 1 citations

  articleOpen accessSenior authorCorresponding

  Friedreich’s ataxia (FRDA) is a neurodegenerative and cardiodegenerative genetic disorder caused primarily by homozygous mutations in the FXN gene, resulting in decreased expression of human mature frataxin (hFXN-M) protein. To test potential new drugs, we developed mutant zebrafish with a deficiency in zebrafish FXN-M (zFXN-M) production by introducing targeted mutations in the z-fxn gene. To validate this model, it was necessary to characterize and quantify zFXN-M protein, but zFXN-M protein could not be detected by Western blot in zebrafish lysates. We developed an alternative strategy involving the use of a stable isotope-labeled internal standard coupled with analysis by high-sensitivity ultrahigh-performance liquid chromatography-multiple reaction monitoring-mass spectrometry (UHPLC-MRM/MS). The endogenous zFXN-M in an internal standard prepared using stable isotope labeling by amino acids in cell culture (SILAC) would have obscured low levels of zFXN-M. In contrast, stable isotope labeling in bacteria (SILIB) provided fully labeled [13C,15N]-zFXN-M with almost undetectable amounts of endogenous protein contamination. This facilitated characterization of amol levels of zFXN-M in zebrafish embryos (120.9 ± 20.1 amol/embryo) and its quantification in intact wild-type fish with levels of 2.26 ± 0.44 ng/mg protein or 145.2 ± 24.5 pg/mg tissue. Recovery of zFXN-M was <10% when the SILIB internal standard was added after isolation, when compared with before isolation. UHPLC-MRM/MS with a SILIB internal standard was the only way to validate zebrafish heterozygous for a knockout mutation in zFXN as a model for FRDA, illustrating its utility for the characterization and quantification of very low abundance tissue proteins.

  PublisherDOI

• Individualized exercise and NAD+ precursor supplementation in Friedreich’s Ataxia: a randomized controlled trial

  SSRN Electronic Journal · 2025-01-01

  preprintOpen access
  PublisherDOI

• Searching for enigmatic biomarkers to address a devastating degenerative disease

  2025-01-01

  article1st authorCorresponding
  PublisherDOI

• Figure S6 from Bile Acid Metabolism Mediates Cholesterol Homeostasis and Promotes Tumorigenesis in Clear Cell Renal Cell Carcinoma

  2024-05-15

  preprintOpen access

  &lt;p&gt;Figure S6&lt;/p&gt;

  PublisherDOI

Recent grants

• NIH Grant P50DK039261

  NIH · $13.1M · 2008

• NIH Grant R01CA091016

  NIH · $2.6M · 2011

• NIH Grant R01CA095586

  NIH · $1.4M · 2008

• NIH Grant P50HL070128

  NIH · $16.7M · 2007

• NIH Grant P50GM015431

  NIH · $33.3M · 2011

Frequent coauthors

• Clementina Mesaros

  431 shared

• Nathaniel W. Snyder

  141 shared

• T.M. Penning

  University of Pennsylvania

  128 shared

• Ronald G. Harvey

  79 shared

• Andrew J. Worth

  Massey University

  77 shared

• Jimmy P. Xu

  68 shared

• David A. Potter

  65 shared

• Seon Hwa Lee

  Tohoku University

  63 shared