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Defining the Role of Epidermal NADPH in Linking Skin Homeostasis to Systemic Metabolism.

Award Number: R01AR086828
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/07/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Defining the Role of Epidermal NADPH in Linking Skin Homeostasis to Systemic Metabolism. - PROJECT SUMMARY: The skin is increasingly recognized as a metabolically active and endocrine organ, yet the pathways that maintain its barrier function and influence whole-body metabolism remain poorly understood. The epidermis must synthesize lipids and maintain antioxidant defenses to protect against reactive oxygen species (ROS). Although oxidative stress has been linked to barrier disruption, how redox imbalance alters epidermal lipid metabolism and whether such disruption influences systemic energy balance remain poorly understood. Both lipid synthesis and antioxidant defense require NADPH, which is generated primarily by the metabolic enzyme NAD kinase (NADK). However, because global NADK deletion is embryonically lethal, the physiological roles of NADK and NADPH metabolism have remained unclear. Using an inducible, keratinocyte- specific NADK knockout mouse model, we discovered that loss of NADK in the skin causes a profound redox imbalance that produces a striking dual phenotype: impaired skin barrier integrity and systemic fat loss with resistance to diet-induced obesity. These systemic effects occur independently of food intake or thermogenesis, revealing a previously unrecognized skin-initiated metabolic signaling pathway. This proposal will test the central hypothesis that epidermal NADPH depletion causes redox imbalance, which (1) disrupts local epidermal lipid metabolism, leading to barrier failure, and (2) activates a redox-dependent skin-to-fat signaling axis that drives systemic lipolysis. Aim 1 will determine how redox imbalance caused by epidermal NADPH depletion leads to disruptions in lipid metabolism, including lipid peroxidation and suppressed de novo lipogenesis, driving barrier failure. We will use isotope tracing, metabolomics, and lipidomics to define the specific metabolic pathways disrupted. Furthermore, we will establish disease relevance by testing this axis in preclinical models of atopic dermatitis (AD) and validating key signatures in human AD patient samples. Aim 2 will elucidate the redox-dependent skin-to-fat signaling axis that drives systemic fat loss. Building on our finding that epidermal redox stress induces skin-derived cytokines that promote lipolysis, we will use complementary genetic and pharmacologic approaches to (1) define the upstream redox-sensitive regulation of cytokine induction in keratinocytes, and (2) delineate the downstream signaling mechanisms through which these cytokines promote adipose loss. By integrating in vivo genetics, in vitro keratinocyte cell culture, redox biochemistry, and advanced metabolic profiling, this work will uncover fundamental principles of redox regulation in the skin and reveal how epidermal metabolism influences systemic energy homeostasis. It will also establish the skin as an endocrine organ that communicates metabolic stress to adipose tissue, advancing a new conceptual framework for skin biology and systemic metabolism. These studies may identify epidermal redox metabolism as a therapeutic target for treating both skin diseases and systemic metabolic disorders.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $578,211 )
2026	2026	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/7/2026	NEW	$578,211
														Subtotal = $578,211

Grand Total All Awards = $578,211

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Defining the Role of Epidermal NADPH in Linking Skin Homeostasis to Systemic Metabolism.

Award Number: R01AR086828

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/07/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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