L32 — Succinate/SUCNR1 insufficiency discussion

Succinate metabolic, inflammatory, BP, and healthspan attributions are often read as SUCNR1/GPR91-necessary because succinate is the endogenous SUCNR1 ligand (He GPR91=succinate receptor + BP abolish in GPR91-deficient; McCreath Sucnr1 LOF metabolic/lipolysis tool; Haffke antagonist tool; Keiran myeloid LOF metabolic obesity) — phenotype, necessity, and tools, not a residual-positive metabolic/healthspan H2H under mammalian Sucnr1 abolish. This discussion asks whether, once SUCNR1/GPR91 LOF or SUCNR1-matched antagonism abolishes SUCNR1-class metabolic/inflammatory/BP attribution, succinate still retains metabolic/healthspan phenotype on the same rodent panel — without inventing residual-positive longevity or treating He BP abolish as residual-positive retain, McCreath/Keiran LOF as residual-positive, or Haffke antagonist as residual H2H.

Claim

On a pre-registered rodent metabolic / early-healthspan / BP-attribution panel (He / McCreath / Haffke / Keiran-class) with exogenous succinate vs vehicle under SUCNR1/GPR91 genetic LOF or SUCNR1-matched antagonism (e.g. NF-56-EJ40-class / Haffke-class) at a lock that abolishes SUCNR1-class metabolic / inflammatory / BP attribution vs SUCNR1-intact concurrent controls, locking SUCNR1-class control benefit abolished under the block arm (primary referee = pre-specified early healthspan/metabolic endpoint within the refute window): under that abolish lock, same-panel early healthspan/metabolic improvement (succinate vs vehicle under abolish) retains ≥50% of the succinate vs vehicle early healthspan/metabolic improvement on SUCNR1-intact concurrent controls on the same panel (named comparator = succinate vs vehicle early healthspan/metabolic Δ on SUCNR1-intact arm; units as pre-specified; α/N pre-specified) — assumption-kill / sucnr1-insufficiency of “succinate metabolic/inflammatory/BP/healthspan = mere SUCNR1-necessary bridge with possible residual.” Residual-positive succinate metabolic/healthspan H2H under mammalian Sucnr1/SUCNR1 abolish = UNKNOWN/EMPTY (do not invent residual longevity/healthspan; Q_resid_life_h2h=0). He Nature GPR91/SUCNR1 = succinate receptor + succinate BP abolished in GPR91-deficient is LITERATURE receptor+ligand foundation + BP-class SUCNR1 necessity — necessity AGAINST residual on BP endpoint ≠ residual-positive retain. McCreath Sucnr1-/- dichotomous obesity/EE + released from succinate lipolysis inhibition is LITERATURE LOF tool + lipolysis-class necessity ≠ residual-positive. Haffke NF-56-EJ40 species-selective SUCNR1 antagonist is LITERATURE structural tool ≠ residual H2H. Keiran myeloid SUCNR1 LOF worsens metabolic obesity is LITERATURE LOF/mechanism ≠ residual-positive succinate-in-KO retain. Adjacent 35097053 acute succinate muscle via SUCNR1 and 40392081 MASH HSC succinate-GPR91 block OUT of public prior_art ≤4 (adjacent / distinctness only). Prefer cell/tissue/block-QC (SUCNR1-class metabolic/inflammatory/BP-attribution QC abolish) before new animal longevity; in vivo early healthspan/metabolic panel remains primary kill path within 4w. Complex II/SDH/HIF non-SUCNR1 path honesty supports possible residual — document; do not invent organismal longevity residual from Complex II/HIF alone. ESPECIALLY ≠L31 (SUCNR1≠HCAR1; succinate≠lactate; Q_L31_tight=0).

Why it matters

Succinate metabolic, inflammatory, BP, and healthspan attributions are often framed as SUCNR1/GPR91–necessary because succinate is the endogenous SUCNR1 ligand (He GPR91=succinate receptor + BP abolish in GPR91-deficient; McCreath Sucnr1 LOF metabolic/lipolysis tool; Haffke antagonist tool; Keiran myeloid LOF metabolic obesity), yet a matched residual-positive succinate metabolic/healthspan H2H under mammalian Sucnr1/SUCNR1 abolish remains UNKNOWN/EMPTY (He BP abolish = necessity AGAINST residual on BP ≠ residual-positive retain; McCreath/Keiran = necessity/tool ≠ residual-positive; Haffke ≠ residual H2H; Complex II/HIF honesty supports possible residual — document; do not invent longevity residual; Q_resid_life_h2h=0). L32 asks whether, once SUCNR1/GPR91 LOF or SUCNR1-matched antagonism abolishes SUCNR1-class metabolic/inflammatory/BP attribution, succinate still retains metabolic/healthspan phenotype on the same panel — metabolic/healthspan ≠ mere SUCNR1-sole-necessity bridge with invented residual longevity. Distinct from L15–L31 insufficiency series and ESPECIALLY L31 (lactate residual under HCAR1/GPR81 — SUCNR1 ≠ HCAR1 CRITICAL; ligand succinate ≠ lactate CRITICAL; Q_L31_tight=0), L30 (BHB residual under HCAR2 — SUCNR1 ≠ HCAR2 CRITICAL; succinate ≠ BHB CRITICAL; Q_L30_tight=1 NON-MATCH), L29 (αKG residual under PHD2 — SUCNR1 ≠ PHD2 CRITICAL), and L28 (taurine residual under TauT — SUCNR1 ≠ TauT CRITICAL); ≠ L27 Klb; ≠ L22 AMPK; NOT NAD-after-senolysis; NOT FOXO4×LOF; NOT MB/MAOI; NOT BPC skip-list. Soft-claims: discussion — residual-positive succinate under SUCNR1 abolish metabolic/healthspan H2H UNKNOWN/EMPTY; longevity/healthspan-class residual EMPTY; BP necessity FOUND (He) ≠ residual; lipolysis/metabolic necessity FOUND (McCreath) ≠ residual; PRIOR_ART PARTIAL (receptor+ligand+BP necessity FOUND; Sucnr1 metabolic LOF tool FOUND; antagonist tool FOUND; myeloid LOF/mechanism FOUND; residual-positive under abolish EMPTY; longevity residual EMPTY); soft-complete empty ≠ novelty / ≠ failure; L1–L31 ≠ proof.

Mechanism sketch

sucnr1-insufficiency assumption-kill: He Nature grounds GPR91/SUCNR1 as the succinate receptor and shows succinate-induced hypertensive effect abolished in GPR91-deficient mice — receptor+ligand foundation + BP-class SUCNR1 necessity ≠ residual-positive succinate retain under SUCNR1 abolish (CRITICAL: BP abolish AGAINST residual on BP); McCreath Diabetes grounds Sucnr1 targeted disruption with dichotomous obesity/energy-expenditure phenotype and Sucnr1(-/-) released from succinate-induced lipolysis inhibition — Sucnr1 genetic LOF metabolic tool + lipolysis-class necessity ≠ residual-positive; Haffke Nature grounds structural basis of species-selective antagonist binding to succinate receptor (human-selective NF-56-EJ40) — SUCNR1-matched antagonist tool ≠ residual H2H; Keiran Nat Immunol grounds SUCNR1 control of anti-inflammatory macrophage program regulating metabolic response to obesity with myeloid SUCNR1 deficiency worsening metabolic obesity — LOF/mechanism replicate ≠ residual-positive succinate-in-KO retain. Prefer cell/tissue/block-QC confirming abolish of SUCNR1-class control (metabolic/inflammatory/BP-attribution QC response abolished) before new animal longevity runs; primary kill path remains a matched rodent ± exogenous succinate ± Sucnr1/SUCNR1 LOF or SUCNR1-matched antagonist at abolish early healthspan/metabolic panel within the refute window; do not invent residual longevity/healthspan; do not treat He BP abolish as residual-positive retain; do not treat McCreath/Keiran LOF as residual-positive; do not treat Haffke as residual H2H; document Complex II/SDH/HIF honesty as caveat without inventing longevity residual; do not collapse to L31 HCAR1 (SUCNR1 ≠ HCAR1; succinate ≠ lactate CRITICAL) or L30 HCAR2 (SUCNR1 ≠ HCAR2; succinate ≠ BHB CRITICAL) or L29 PHD2 (SUCNR1 ≠ PHD2) or L28 TauT (SUCNR1 ≠ TauT) or L27 Klb (SUCNR1 ≠ Klb) or L22 AMPK (SUCNR1 ≠ AMPK primary). Competing caveats: abolish-fail (block not actually abolishing SUCNR1-class control benefit) / succinate-alone-null on SUCNR1-intact arm / underpowered strata / referee-assay mismatch vs He/McCreath/Haffke/Keiran-class lock / Complex-II-or-HIF-confound-without-selective-confirmation leave the test inconclusive rather than refuted; soft-complete empty ≠ novelty / ≠ failure; L15–L31 ≠ this; ESPECIALLY L31 ≠ this (SUCNR1 ≠ HCAR1 CRITICAL; succinate ≠ lactate CRITICAL); L30 ≠ this (SUCNR1 ≠ HCAR2 CRITICAL); L29 ≠ this (SUCNR1 ≠ PHD2 CRITICAL); L28 ≠ this (SUCNR1 ≠ TauT CRITICAL). NOT NAD-after-senolysis (SERIES_FROZEN). Do not invent residual effect sizes or KD/IC50.

Prior art

• PMID 15141213 / DOI 10.1038/nature02488 — He: citric acid cycle intermediates as ligands for orphan GPCRs; GPR91/SUCNR1 = succinate receptor; succinate increases blood pressure; succinate-induced hypertensive effect abolished in GPR91-deficient mice — receptor+ligand foundation + BP-class SUCNR1 necessity AGAINST residual on BP; ≠ residual-positive succinate retain under SUCNR1 abolish.
• PMID 25352636 / DOI 10.2337/db14-0346 — McCreath: targeted disruption of the SUCNR1 metabolic receptor leads to dichotomous effects on obesity; Sucnr1(-/-) released from succinate-induced inhibition of lipolysis — Sucnr1 genetic LOF metabolic tool + lipolysis-class necessity; ≠ residual-positive succinate retain under Sucnr1 abolish.
• PMID 31645725 / DOI 10.1038/s41586-019-1663-8 — Haffke: structural basis of species-selective antagonist binding to the succinate receptor; human-selective antagonist NF-56-EJ40 — SUCNR1 antagonist structural tool; ≠ residual-positive H2H.
• PMID 30962591 / DOI 10.1038/s41590-019-0372-7 — Keiran: SUCNR1 controls an anti-inflammatory program in macrophages to regulate the metabolic response to obesity; myeloid SUCNR1 deficiency worsens metabolic obesity — LOF/mechanism replicate; ≠ residual-positive succinate-in-KO retain.

Baseline claimed

Under SUCNR1/GPR91 genetic LOF or SUCNR1-matched antagonism that abolishes SUCNR1-class metabolic / inflammatory / BP attribution, succinate still retains metabolic / healthspan phenotype on the same panel — or He 2004 settles residual-positive under GPR91 abolish / invents residual from BP abolish / McCreath 2015 proves residual-positive succinate-in-KO retain / Haffke 2019 settles residual H2H / Keiran 2019 proves residual-positive succinate-in-KO retain / Complex II/HIF co-mention invents measured organismal longevity residual / 35097053 invents residual under abolish / 40392081 collapses L32→L30 / L15 Oh organ-age / L16 tissue-vs-blood under D+Q / L17 intermittent-rapa FKBP / L18 17α-E2 caloric-match / L19 acarbose glycemic-match / L20 SPD/ATG bulk autophagy / L21 UA/mitophagy / L22 metformin/AMPK / L23 lithium/GSK3 / L24 canagliflozin/SGLT2 / L25 resveratrol/SIRT1 / L26 melatonin/MT / L27 FGF21/Klb / L28 taurine/TauT / L29 αKG/PHD2 / L30 BHB/HCAR2 / L31 lactate/HCAR1 / L1–L31 already settle the residual H2H.

Baseline measured

He GPR91/SUCNR1 = succinate receptor + succinate BP abolished in GPR91-deficient LITERATURE receptor+ligand + BP necessity — necessity AGAINST residual on BP ≠ residual-positive retain (PMID 15141213). McCreath Sucnr1-/- dichotomous obesity/EE + released from succinate lipolysis inhibition LITERATURE LOF tool + lipolysis necessity ≠ residual-positive (PMID 25352636). Haffke NF-56-EJ40 species-selective antagonist LITERATURE structural tool ≠ residual H2H (PMID 31645725). Keiran myeloid SUCNR1 LOF worsens metabolic obesity LITERATURE LOF/mechanism ≠ residual-positive succinate-in-KO retain (PMID 30962591). Adjacent 35097053 acute succinate muscle via SUCNR1 LITERATURE adjacent — intact SUCNR1 expected; ≠ residual under abolish — OUT of public prior_art ≤4. Adjacent 40392081 MASH HSC succinate-GPR91 block LITERATURE adjacent distinctness Q_L30_tight NON-MATCH supporting SUCNR1 ≠ HCAR2 — OUT of public prior_art ≤4. Complex II/SDH/HIF non-SUCNR1 path LITERATURE honesty supporting possible residual — do not invent longevity residual. Residual-positive succinate metabolic/healthspan H2H under Sucnr1/SUCNR1 abolish that abolishes SUCNR1-class control UNKNOWN/EMPTY (soft-complete Q_resid_life_h2h=0 EMPTY; BP necessity FOUND; lipolysis/metabolic necessity FOUND). Block-arm early healthspan/metabolic improvement retains ≥50% of SUCNR1-intact succinate vs vehicle early healthspan/metabolic improvement PREDICTION. L15 ≠ L32; L16 ≠ L32; L17 ≠ L32; L18 ≠ L32; L19 ≠ L32; L20 ≠ L32 (SUCNR1 ≠ bulk ATG); L21 ≠ L32 (SUCNR1 ≠ mitophagy); L22 ≠ L32 (SUCNR1 ≠ AMPK primary); L23 ≠ L32 (SUCNR1 ≠ GSK3); L24 ≠ L32 (SUCNR1 ≠ SGLT2); L25 ≠ L32 (SUCNR1 ≠ SIRT1); L26 ≠ L32 (SUCNR1 ≠ MT/melatonin); L27 ≠ L32 (SUCNR1 ≠ Klb/FGFR1 CRITICAL); L28 ≠ L32 (SUCNR1 ≠ TauT CRITICAL); L29 ≠ L32 (SUCNR1 ≠ PHD2 CRITICAL); L30 ≠ L32 (SUCNR1 ≠ HCAR2 CRITICAL; succinate ≠ BHB CRITICAL; Q_L30_tight=1 NON-MATCH); L31 ≠ L32 (SUCNR1 ≠ HCAR1 CRITICAL; succinate ≠ lactate CRITICAL; Q_L31_tight=0 NON-MATCH); L1–L31 ≠ proof — soft-complete empty ≠ novelty / ≠ failure. NOT NAD-after-senolysis. Do not invent residual longevity.

Actionable limitations

1. Do not treat L1–L31 as proving L32 — new parent area succinate-sucnr1-insufficiency; He/McCreath/Haffke/Keiran layers are receptor+ligand/BP necessity or Sucnr1 metabolic LOF tool or antagonist tool or myeloid LOF/mechanism, not residual-positive H2H under mammalian Sucnr1 abolish for metabolic/healthspan class; soft-complete empty ≠ demonstrated prediction-failure; do not invent residual longevity; do not treat He BP abolish as residual-positive retain; do not treat McCreath/Keiran as residual-positive; do not treat Haffke as residual H2H; do not collapse to L31 HCAR1 (SUCNR1 ≠ HCAR1; succinate ≠ lactate CRITICAL) or L30 HCAR2 (SUCNR1 ≠ HCAR2; succinate ≠ BHB CRITICAL) or L29 PHD2 (SUCNR1 ≠ PHD2) or L28 TauT (SUCNR1 ≠ TauT) or L27 Klb (SUCNR1 ≠ Klb).
2. 15141213 is BP necessity AGAINST residual on BP ≠ residual-positive retain; 25352636 is Sucnr1 LOF metabolic/lipolysis necessity/tool ≠ residual-positive; 31645725 is antagonist tool ≠ residual H2H; 30962591 is myeloid LOF/mechanism ≠ residual-positive succinate-in-KO; 35097053/40392081 adjacent OUT of public prior_art; matched residual-positive succinate metabolic/healthspan H2H UNKNOWN/EMPTY; longevity/healthspan-class residual EMPTY — PRIOR_ART PARTIAL.
3. L15 ≠ L32; L16 ≠ L32; L17 ≠ L32; L18 ≠ L32; L19 ≠ L32; L20 ≠ L32 (SUCNR1 ≠ bulk ATG); L21 ≠ L32 (SUCNR1 ≠ mitophagy); L22 ≠ L32 (SUCNR1 ≠ AMPK); L23 ≠ L32 (SUCNR1 ≠ GSK3); L24 ≠ L32 (SUCNR1 ≠ SGLT2); L25 ≠ L32 (SUCNR1 ≠ SIRT1); L26 ≠ L32 (SUCNR1 ≠ MT); L27 ≠ L32 (SUCNR1 ≠ Klb CRITICAL); L28 ≠ L32 (SUCNR1 ≠ TauT CRITICAL); L29 ≠ L32 (SUCNR1 ≠ PHD2 CRITICAL); L30 ≠ L32 (SUCNR1 ≠ HCAR2 CRITICAL; succinate ≠ BHB CRITICAL); L31 ≠ L32 (SUCNR1 ≠ HCAR1 CRITICAL; succinate ≠ lactate CRITICAL; Q_L31_tight=0); NAD/CD38/senolysis soft-complete NON-MATCH — NOT SERIES_FROZEN NAD-after-senolysis; no dosing; ip_class ≠ none; orthosteric_drift=false.

Method

propose-assay

Labels

status_labels: [NEGATIVE] novelty_tag: assumption-kill polarity: negative openlabs_target: discussion openlabs_topic: biology-life-sciences tags: metabolic-health, longevity risk_class: research-discussion

Prediction variables

Ablate

• remove matched succinate ± Sucnr1/SUCNR1 LOF (or SUCNR1-matched antagonism abolishing SUCNR1-class control) vs SUCNR1-intact concurrent controls with same-panel early healthspan/metabolic residual co-readout: Without the abolish-lock × residual healthspan/metabolic H2H on the same panel, separate He receptor+ligand/BP-necessity LITERATURE and McCreath/Haffke/Keiran tool LITERATURE cannot show metabolic/healthspan ≠ mere SUCNR1-sole-necessity bridge, and residual-positive succinate metabolic/healthspan stays untested (not invented).
• remove block-arm early healthspan/metabolic improvement scored against the SUCNR1-intact succinate vs vehicle early healthspan/metabolic improvement as named comparator under the abolished-control lock (vs phenotype-alone): Without the intact-arm succinate vs vehicle early healthspan/metabolic comparator under the abolish lock, the card collapses into unmatched phenotype framing and loses the sucnr1-insufficiency assumption-kill.
• remove L15≠L32 + L16≠L32 + L17≠L32 + L18≠L32 + L19≠L32 + L20≠L32 + L21≠L32 + L22≠L32 + L23≠L32 + L24≠L32 + L25≠L32 + L26≠L32 + L27≠L32 + L28≠L32 + L29≠L32 + L30≠L32 + L31≠L32 + L1–L31≠proof + soft-complete-empty≠novelty + residual-longevity-UNKNOWN + He≠residual-positive + McCreath/Keiran≠residual-positive + Haffke≠residual + ComplexII_HIF≠invented-longevity + SUCNR1≠HCAR1 + SUCNR1≠HCAR2 + SUCNR1≠PHD2 + SUCNR1≠TauT + SUCNR1≠Klb + succinate≠lactate + succinate≠BHB + NOT-NAD-after-senolysis discipline: Treating L15 Oh organ-age, L16 tissue-vs-blood, L17 intermittent-rapa FKBP, L18 caloric-match, L19 glycemic-match, L20 SPD/ATG, L21 UA/mitophagy, L22 metformin/AMPK, L23 lithium/GSK3, L24 canagliflozin/SGLT2, L25 resveratrol/SIRT1, L26 melatonin/MT, L27 FGF21/Klb (via SUCNR1≠Klb collapse), L28 taurine/TauT (via SUCNR1≠TauT collapse), L29 αKG/PHD2 (via SUCNR1≠PHD2 collapse), L30 BHB/HCAR2 (via SUCNR1≠HCAR2 or succinate≠BHB collapse), L31 lactate/HCAR1 (via SUCNR1≠HCAR1 or succinate≠lactate collapse CRITICAL), He BP abolish as residual-positive retain, McCreath/Keiran as residual-positive, Haffke as residual H2H, Complex II/HIF co-mention as invented longevity residual, empty PubMed, or NAD/CD38 adjacent hits as already deciding residual-positive under mammalian Sucnr1 abolish — or inventing residual effect sizes — would invent a result left UNKNOWN.

Refute if

On the pre-registered rodent metabolic / early-healthspan / BP-attribution panel (He / McCreath / Haffke / Keiran-class) where Sucnr1/SUCNR1 LOF or SUCNR1-matched antagonism locks SUCNR1-class control benefit abolished, same-panel early healthspan/metabolic improvement (succinate vs vehicle under abolish) is <50% of the succinate vs vehicle early healthspan/metabolic improvement on SUCNR1-intact concurrent controls — so succinate metabolic/inflammatory/BP/healthspan DOES reduce to mere SUCNR1-necessary bridge under abolished SUCNR1-class control and the sucnr1-insufficiency assumption-kill fails — when abolish-fail, succinate-alone-null, underpowered-strata, assay-mismatch, or Complex-II-or-HIF-confound-without-selective-confirmation artifacts that would otherwise leave the test inconclusive are ruled out.

Ask a human

Lock one rodent exogenous succinate vs vehicle × Sucnr1/SUCNR1 LOF or SUCNR1-matched antagonism regimen with abolished SUCNR1-class-control-benefit definition, prefer cell/tissue/block-QC (SUCNR1-class metabolic/inflammatory/BP-attribution QC abolish) before new animal longevity, primary early healthspan/metabolic referee within the refute window, and ≥50%-of-intact-succinate-vs-vehicle early healthspan/metabolic retention gate before claiming residual under SUCNR1 abolish; do not invent residual longevity; do not treat He BP abolish as residual-positive retain or McCreath/Keiran as residual-positive or Haffke as residual H2H or Complex II/HIF as invented longevity residual or 35097053/40392081 as residual-positive under abolish or L15 or L16 or L17 or L18 or L19 or L20 or L21 or L22 or L23 or L24 or L25 or L26 or L27 or L28 or L29 or L30 or L31 or L1–L31 as residual-positive metabolic/healthspan proof; SUCNR1 ≠ HCAR1; SUCNR1 ≠ HCAR2; SUCNR1 ≠ PHD2; SUCNR1 ≠ TauT; SUCNR1 ≠ Klb/FGFR1; SUCNR1 ≠ MT/melatonin; SUCNR1 ≠ SIRT1; SUCNR1 ≠ bulk ATG; SUCNR1 ≠ mitophagy; SUCNR1 ≠ GSK3; SUCNR1 ≠ SGLT2; SUCNR1 ≠ AMPK primary; succinate ≠ lactate; succinate ≠ BHB; He BP abolish ≠ residual-positive retain; NOT NAD-after-senolysis; no dosing.

Cheap IP

kill_cost_tier=1 · time_to_refute=4w · ip_class=sucnr1-insufficiency · vault_hold=no

Execution

execution_status=NOT_RUN · fto_status=UNKNOWN · related_prior=He 2004 GPR91/SUCNR1 = succinate receptor + BP abolish in GPR91-deficient (Nature) × McCreath 2015 Sucnr1 targeted disruption dichotomous obesity/EE LOF tool (Diabetes) × Haffke 2019 structural species-selective antagonist NF-56-EJ40 (Nature) × Keiran 2019 SUCNR1 anti-inflammatory macrophage / metabolic obesity myeloid LOF (Nat Immunol) — 35097053 adjacent OUT of public prior_art — 40392081 adjacent distinctness OUT of public prior_art — Complex II/SDH/HIF caveat — L15 (DunedinPACE-without-GrimAge × Oh organ-age — not succinate SUCNR1-block residual; L15 ≠ L32); L16 (tissue SA-β-gal/p16 vs blood under D+Q — not sucnr1-insufficiency residual; L16 ≠ L32); L17 (intermittent-rapa FKBP-high tissue mTORC2 — not SUCNR1; L17 ≠ L32); L18 (17α-E2 × caloric-match residual — different drug/modality; L18 ≠ L32); L19 (acarbose × glycemic-match residual — different drug/modality; L19 ≠ L32); L20 (SPD residual under ATG5/7 / autophagy-insufficiency — SUCNR1 ≠ bulk ATG; L20 ≠ L32); L21 (UA residual under PINK1/Parkin / mitophagy-insufficiency — SUCNR1 ≠ mitophagy; L21 ≠ L32); L22 (metformin residual under AMPK LOF/Compound C / ampk-insufficiency — SUCNR1 ≠ AMPK primary; L22 ≠ L32); L23 (lithium residual under GSK3 LOF / gsk3-insufficiency — SUCNR1 ≠ GSK3; L23 ≠ L32); L24 (canagliflozin residual under SGLT2 LOF / sglt2-insufficiency — SUCNR1 ≠ SGLT2; L24 ≠ L32); L25 (resveratrol residual under SIRT1 LOF/EX527 / sirt1-insufficiency — SUCNR1 ≠ SIRT1; L25 ≠ L32); L26 (melatonin residual under luzindole/Mtnr1a/b / mt-receptor-insufficiency — SUCNR1 ≠ MT/melatonin; L26 ≠ L32); L27 (FGF21 residual under Klb/FGFR1 / klb-insufficiency — SUCNR1 ≠ Klb/FGFR1 CRITICAL; L27 ≠ L32); L28 (taurine residual under TauT/Slc6a6 / taut-insufficiency — SUCNR1 ≠ TauT CRITICAL; L28 ≠ L32); L29 (αKG residual under PHD2/Egln1 / phd-insufficiency — SUCNR1 ≠ PHD2 CRITICAL; L29 ≠ L32); L30 (BHB residual under HCAR2/GPR109A/PUMA-G / hcar2-insufficiency — SUCNR1 ≠ HCAR2 CRITICAL; succinate ≠ BHB CRITICAL; Q_L30_tight=1 NON-MATCH; L30 ≠ L32); L31 (lactate residual under HCAR1/GPR81 / hcar1-insufficiency — SUCNR1 ≠ HCAR1 CRITICAL; succinate ≠ lactate CRITICAL; Q_L31_tight=0 NON-MATCH; L31 ≠ L32); L1–L31 ≠ proof