Methods and Compositions for Treatment and Patient Stratification of Fibrotic Disease by Reversal or Reprogramming of an SPP1-Positive, TREM2-Marked Lipid-Sensing Profibrotic Macrophage Cell State (Provisional Patent Specification)

Specification of U.S. Provisional Patent Application No. 64/129,001 (filed August 10, 2026; inventor Glen Charles Ritschel, Ritschel Research), archived as a citable, timestamped defensive-publication disclosure. This disclosure describes a single-cell RNA-sequencing-derived signature of an SPP1-positive, TREM2-marked, lipid-sensing, monocyte-derived profibrotic macrophage — the scar-associated macrophage that displaces the resident homeostatic tissue macrophage and drives fibroblast activation — and a method of treating, stratifying, and reversing or reprogramming that cell state across a genus of fibrotic diseases. Scored in one uniform analysis of independent public human single-cell datasets, the macrophage program is elevated in systemic sclerosis interstitial lung disease (program gain ~+0.72, ~94% of signature genes concordantly elevated), idiopathic pulmonary fibrosis (~+0.10, ~78%), and cirrhotic liver (~+0.08, ~76%), in every case led by SPP1, with the amplitude set by the lipid content of the resident-macrophage baseline while the pathogenic target stays constant. The disclosure provides the 18-gene signature; a method of measuring the cell state in the myeloid compartment; a method of selecting agents that reverse or reprogram it (PPAR-gamma agonists, liver-X-receptor and lipid-efflux modulators, SPP1/osteopontin-axis inhibitors, CCR2 antagonists, and TREM2-directed biologics), optionally in combination with a fibroblast-directed antifibrotic that targets the myofibroblast effector of the same disease; and a stratification biomarker defining a responder subgroup. The genus is deliberately limited to organs where the state is validated as expanded (lung, liver). Discovery-stage computational work: the disease-associated expansion is validated in independent public human single-cell data, while reversal or reprogramming by the named agents is mechanism-anchored and not yet demonstrated preclinically or clinically. Not medical or legal advice.