Aberrant protein folding/clearance in cardiomyocytes, via ubiquitin‐proteasome system (UPS) insufficiency, contributes to cardiomyopathy; however, our lab’s new data challenges this paradigm. Prior rodent studies show that UPS inhibition (pharmacologic and genetic) causes accumulation of misfolded/ubiquitinated proteins, decreased proteasomal activities, worse outcomes to cardiac stress, and premature death. Conversely, gain‐of‐function models enhancing UPS efficiency improve cardiac function.We discovered an exception to these associations while characterizing TXLNB, a muscle‐enriched protein with predominant perinuclear localization and unknown function. Surprisingly, despite severe cardiac UPS insufficiency, TXLNB knockout (TXLNB‐KO) mice exhibit normal cardiac function (Echo/EKG/LV‐Cath) up to 2 years‐old. In cardiomyocytes, TXLNB overexpression decreased ubiquitinated proteins and increased proteasome activity, whereas knockdown promotes proteasomal insufficiency. Similarly, hearts from young and old TXLNB‐KO mice show robust accumulation of ubiquitinated proteins (>2‐fold) and decreased 26SB5 proteasome activity (~40%), similar to other UPS‐disruption models that show overt cardiac dysfunction (e.g. CRYAB‐R120G).Next, to test if cardiotoxic UPS dysfunction intersects with TXLNB actions, TXLNB‐KO mice were crossed to CRYAB‐R120G transgenic mice and heart functions measured in mixed‐sex cohorts for one year. Our data show CRYAB mice present with characteristic bi‐ventricular hypertrophy that slowly progresses to heart failure (EF = 56% at 36 weeks age, n=28), with intracardiac thrombi, pericardial effusion, pulmonary edema, and early death (median survival=41.8 weeks). Combined TXLNB‐KO / CRYAB mice trended to worse cardiac function (EF =46% at 36 weeks age, n=16, p=0.057 compared to CRYAB only), however end‐stage heart failure remained unchanged (median survival=42.7).Next, to test if TXLNB overexpression could improve CRYAB‐induced proteotoxicity, we created an AAV2/9 virus that expresses TXLNB under control of cardiac Troponin T promoter (cTnT), capable of 6‐fold overexpression in hearts. Wild‐type and CRYAB mice at 3 weeks old were injected via jugular vein with AAV2/9 cTnT‐TXLNB (n=6) or cTNT‐GFP (n=6) virus and monitored until 25 weeks age. EKG, Echocardiography, and post‐mortem gravimetric results show that TXLNB overexpression does not reduce biventricular hypertrophy, or improve cardiac functions caused by CRYAB‐R120G. Ongoing work is evaluating if TXLNB overexpression restores any molecular deficiencies caused by CRYAB‐R120G (proteasome insufficiency, ubiquitinated protein load, oxidized proteins, etc).Together, these findings suggest that TXLNB regulation of the UPS and cardiomyopathy from proteotoxic stress exist separately, and the understood relationship between UPS insufficiency and cardiomyopathy remains unclear. We think the prominent perinuclear location of TXLNB indicates a role in UPS regulation at microtubule centers and may associate with redistributed centrosomal proteins in cardiomyocytes. Ongoing work will address the “where” and/or the “what” (regarding accumulated ubiquitinated proteins) that dictate pathological/protective responses.Support or Funding Information19POST34380640 to JMM and HL144717, HL148796 to RLB